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Neuroblastoma
Clinical and Surgical

Management
Sabine Sarnacki
Luca Pio
Editors
123
Neuroblastoma
Sabine Sarnacki • Luca Pio
Editors
Neuroblastoma
Clinical and Surgical Management
Editors
Sabine Sarnacki Luca Pio
Department of Pediatric Surgery Department of Pediatric Surgery
Necker - Enfants Malades Hospital Necker - Enfants Malades Hospital
Assistance Publique Hopitaux de Paris Assistance Publique Hopitaux de Paris
University of Paris University of Paris
Paris Paris
France France
ISBN 978-3-030-18395-0 ISBN 978-3-030-18396-7 (eBook)

https://doi.org/10.1007/978-3-030-18396-7
© Springer Nature Switzerland AG 2020

This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of
the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation,
broadcasting, reproduction on microfilms or in any other physical way, and transmission or information
storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology
now known or hereafter developed.
The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication
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protective laws and regulations and therefore free for general use.
The publisher, the authors, and the editors are safe to assume that the advice and information in this book
are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the
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in published maps and institutional affiliations.
This Springer imprint is published by the registered company Springer Nature Switzerland AG
The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland
Foreword
Sabine Sarnacki and Luca Pio have created a comprehensive text on neuroblastoma.
This is a timely submission. The roster of authors are all international experts on the
diagnosis and management of neuroblastoma. Drs. Sarnacki and Pio have compiled
a text that provides information extending from the epidemiology of this disease to
its imaging and, most importantly, the clinical management and surgery. This text
will provide the reader a single source of the most current knowledge on all aspects
of neuroblastoma. They are to be congratulated for this singular effort providing us
a veritable wealth of information on neuroblastoma. I believe it will serve as an
invaluable reference text for readers of all levels.
Robert C. Shamberger
Surgery, Boston Children’s Hospital
Harvard Medical School
Harvard, MA, USA
Robert E. Gross
Professor of Surgery
Harvard Medical School
Harvard, MA, USA
Chief of Surgery
Boston Children’s Hospital
Boston, MA, USA
v
Contents
Part I Epidemiology, Biology and Pathology Assessment

1 Epidemiology�� 3
Jacqueline Clavel, Brigitte Lacour, and Paula Rios
2 Biology of Neuroblastoma �� 17
Gudrun Schleiermacher
3 Neuroblastoma Pathogenesis�� 29
Isabelle Janoueix-Lerosey
4 Neuroblastoma Pathology �� 57
Hiroyuki Shimada, Angela R. Sementa, Bruce R. Pawel,
and Naohiko Ikegaki
Part II Imaging
5 Radiology�� 87
Hervé J. Brisse, Martijn Verhagen, Kieran McHugh,
and Claudio Granata
6 Image-Defined Risk Factors�� 119
Giovanni Cecchetto, Tom Monclair, and Hervé J. Brisse
7 Nuclear Medicine Procedures in Neuroblastoma�� 139
Arnoldo Piccardo, Rita Castellani, Gianluca Bottoni,
Michela Massollo, Giulia Anna Follacchio, and Egesta Lopci
8 Radiotherapy for Neuroblastoma�� 163
Tom Boterberg
Part III Clinical Management

9 Spinal Canal Involvement in Peripheral Neuroblastic Tumors �� 173
Shifra Ash, Stefania Sorrentino, Kathelijne Kraal,
and Bruno De Bernardi
10 Neonatal Neuroblastoma �� 191
Dominique Plantaz and Claire Freycon
vii
viii Contents
11 Low- and Intermediate-Risk Neuroblastoma�� 205

Vanessa Segura and Adela Cañete
12 High-Risk Neuroblastoma and Current Protocols�� 213
Katherine K. Matthay and Dominique Valteau-Couanet
13 Immunotherapy�� 237
Francesca del Bufalo and Franco Locatelli
14 Prognostic Factors and Risk Stratification�� 271
Meredith S. Irwin
Part IV Surgery
15 Biopsy of Neuroblastoma�� 295
Dhanya Mullassery, Laurence Abernethy, Rajeev Shukla,
and Paul D. Losty
16 Surgical Techniques �� 313
James A. Saltsman III, Nicole J. Croteau, and Michael P. LaQuaglia
17 Surgical Strategies for High Risk Neuroblastoma�� 327
Sanjeev A. Vasudevan and Jed G. Nuchtern
18 Surgical Strategies for Neuroblastoma with Spinal
Canal Involvement �� 337
Luca Pio, Thomas Blanc, Christophe Glorion, Stephanie Puget,
Michel Zerah, and Sabine Sarnacki
19 Neuroblastoma: Minimally Invasive Surgery�� 343
Jörg Fuchs and Steven W. Warmann
20 Robotic Surgery for Neuroblastoma�� 357
Luca Pio, Thomas Blanc, Girolamo Mattioli, Yves Heloury,
and Sabine Sarnacki
21 Complications of the Surgical Management of Children
with Neuroblastoma�� 363
Andrew M. Davidoff
22 Palliative Care�� 375
Alessandro Inserra and Alessandro Crocoli
Part I
Epidemiology, Biology and
Pathology Assessment
Epidemiology
1
Jacqueline Clavel, Brigitte Lacour, and Paula Rios
Neuroblastomas are rare diseases, and as such their surveillance requires specific
large-scale reliable population registries. We are more and more able to describe
neuroblastomas and other embryonal tumors all over the world, but information is
still insufficient and fragile in low-income countries, now prioritized in the interna-
tional strategies of cancer surveillance. Epidemiological research on risk factors,
also, is limited by the rarity of the disease and mostly relies on case–control studies,
that is, studies performed at the time of diagnosis, getting information by interview
and, in some countries, from databases like birth certificates. Lack of knowledge
about risk factors is important, and the international epidemiology consortiums are
currently strengthening their efforts on etiological research.
1.1 Descriptive Epidemiology
In the International classification of disease for oncology (ICD-O-3) [1], neuroblas-

tomas are classified into the two morphologic codes 95003 (neuroblastoma, the most
frequent) and 94903 (ganglioneuroblastoma, the best differentiated form of neuro-
blastoma). Both are grouped in the category IV (Tumors), subgroup IV.a (neuroblas-
tomas) of the International classification for childhood cancers (ICCC) [2].
J. Clavel (*) · B. Lacour

CRESS, UMRS1153, INSERM, Université Paris-Descartes, Paris, France
National Registry of Childhood Cancers, APHP Hôpital Paul Brousse, Villejuif, France
CHU de Nancy, Vandoeuvre-lès-Nancy, France
e-mail: jacqueline.clavel@inserm.fr
P. Rios
CRESS, UMRS1153, INSERM, Université Paris-Descartes, Paris, France
© Springer Nature Switzerland AG 2020 3

S. Sarnacki, L. Pio (eds.), Neuroblastoma,
https://doi.org/10.1007/978-3-030-18396-7_1
4 J. Clavel et al.
In this chapter, the epidemiological features of neuroblastomas are described

using the 2000–2013 data extracted from the French National Registry of Childhood
Cancer (RNCE) (http://rnce.inserm.fr). The RNCE registers 130–150 new cases of
neuroblastoma aged under 15 years every year.
1.1.1 Incidence and Epidemiological Features
The annual age-standardized incidence rate is around 14 cases per million of children
aged 0–14 years (Table 1.1). Neuroblastomas are mostly diagnosed before the age of
5 years (85%), and 40% occur in infancy. They are very uncommon after the age of
10 years. Annual incidence rates vary from 73 cases per million in infancy to 1 case
per million after the age of 10 years. Neuroblastomas are the most frequent tumors
diagnosed in neonates (<28 days). One out of ten cases of neuroblastomas is neonate.
Most of them (65%) are diagnosed before birth by routine ultrasonography.
According to ICD-O categories, 11% of the French cases are ganglioneuroblasto-
mas and 89% are neuroblastomas. Half of the tumors are located in the adrenal glands,
20% in other abdominal sites, 16% in mediastinum, and the remaining 15% are dis-
tributed in pelvis, cervical, or lumbar chains of the sympathetic nervous system.
Almost half of the cases have distant metastases at diagnosis. The proportion is
smaller in infants, but most of them (nearly a quarter of the cases under 1 year) are stage
4S, a specific pattern of metastatic disease spread to skin, liver, and bone marrow.
Amplification of MYCN oncogene is present in less than 10% of infant neuro-
blastomas, but in more than 20% of neuroblastomas after the age of 1 year.
In France, incidence has remained stable since 2000, and no spatial heterogene-
ity has been observed. Increase in incidence has been reported for Europe as a whole
over the earlier period of 1978–1997 with an average change of 1.5% per year [3].
Table 1.1 Number of cases of neuroblastomas and annual incidence rates in France from 2000 to
2013, by age groups, according to MYCN status and tumoral extension
Age groups (years)
<1 1–4 5–9 10–14 Total
Incidence rate
IR (/million year) 73.1 22.2 4.0 1.1 12.5
ASR (/million year) 14.1
Mean annual numbers 55 67 15 4 141
39.0% 47.5% 10.6% 2.8% 100.0%
MYCN amplification
Amplified 7.2% 26.4% 16.6%
Nonamplified 78.1% 59.8% 67.8%
Unknown 14.7% 13.8% 15.6%
Tumoral extension
Nonmetastatic 61.7% 44.8% 49.1% 44.3% 51.8%
Metastatic not 4S 24.4% 54.9% 50.5% 55.7% 42.6%
Metastatic 4S 13.9% 0.2% 5.6%
IR incidence rate, ASR age standardized rate
1 Epidemiology 5
Table 1.2 Five-year overall survival by age groups, according to MYCN status and tumoral exten-
sion (France, 2000–2013)
5-year survival [95% CI]
<1 year old ≥1 year old Total
Total 90.3 [88.0–92.2] 66.0 [63.2–68.7] 75.3 [73.3–77.2]
MYCN
Amplified 40.0 [27.0–52.7] 44.1 [38.0–50.0] 43.3 [37.8–48.7]
Nonamplified 95.1 [93.1–96.6] 71.9 [68.4–75.2] 82.4 [80.2–84.4]
Unknown 89.4 [82.1–93.8] 71.7 [64.6–77.6] 78.1 [72.9–82.4]
Tumor extension
Nonmetastatic 96.5 [94.3–97.8] 89.7 [86.6–92.2] 93.0 [91.1–94.4]
Metastatic not 4S 71.3 [61.4–79.1] 45.2 [41.2–49.2] 48.7 [44.9–52.4]
Metastatic 4S 84.6 [78.6–89.0] 48.6 [19.2–73.0] 82.5 [76.5–87.1]
The highest incidence rates have been reported in countries with greater medical
surveillance such as western Europe, the USA, Canada, Japan, and Australia which
may reflect better diagnostic facilities [4]. Incidence rates reported by low- and
medium-resource countries are generally lower, which may reflect true risk factors,
as well as differences in diagnosis and registration practices [5, 6]. Racial differ-
ences have been suggested in previous periods. Nevertheless, annual incidence rate
in black children in the USA is now 10.2 per million for 2001–2010, closer to that
of white children, while very low rates are reported in the mostly black population
of Sub-Saharan Africa [6].
1.1.2 Survival
The overall survival rates in France are 92% at 1 year and 75% at 5 years after diag-
nosis (Table 1.2). Survival varies strongly with age, with best figures among infants.
MYCN amplification and metastases are associated with poor prognosis.
Treatment protocols have followed one another over the last 40 years to better
account for poor prognostic factors and to intensify the treatment of high-risk
groups [4, 7, 8]. However, recent data show a stagnation and even a significant fall
in survival for neuroblastoma in Central Europe [9] and the USA [10].
There are still survival disparities between countries, even within Europe [9]. A
5-year overall survival estimate of 59% was recently reported for Southern and
Eastern European countries [11]. Disparities could be, at least partly, attributed to
differences in detection or registration since more elaborate healthcare systems may
capture more low-risk cases, including, for example, spontaneously regressive cases.
1.2 Etiology
Because neuroblastoma is rare, literature on etiology is more limited than for leuke-
mia or brain tumors, and studies often lack power. The characteristics of the cells
6 J. Clavel et al.
and the early onset suggest a role of genetic factors and perinatal exposures. In rare
cases, neuroblastoma can occur in a context of malformation syndromes (e.g.
Hirschsprung’s disease) or genetic diseases (e.g. neurofibromatosis type 1) and pre-
disposing constitutional mutations (e.g. NF1, ALK, or PHOXB). These factors are
addressed in Sect. 1.1.2. So far, genetic studies are still rare for low-risk low-
penetrance susceptibility alleles, and neither gene–environment interactions, nor
epigenetic effects of environment are covered yet.
1.2.1 Perinatal Characteristics
1.2.1.1 Gestational Age, Birth Weight, and Size for Gestational Age
Several case–control studies have analyzed the relationship between gestational
age, birth weight, and neuroblastoma, some of them based on maternal interview at
the time of diagnosis [12–16] and some using information from birth certificates
[17–22]. They are summarized in Table 1.3.
Table 1.3 Relative risk estimates for the association between neuroblastoma and birth
characteristics
Study Exposure Prevalence Reference group OR [95% CI]
Interview-based case–control studies
US-Canada, <32 weeks 2% 37–42 weeks 1.9 [0.7–4.4]
1992–1994 33–36 weeks 6% 0.5 [0.3–1.0]
504 cases >42 weeks 1% 0.9 [0.3–3.0]
<19 years [12] <1500 g 1% 2501–4000 g 2.6 [0.7–10.3]
1500–2500 g 6% 1.1 [0.6–2.0]
4001–4499 g 11% 1.1 [0.7–1.7]
≥4500 g 1% 1.4 [0.6–3.2]
Germany, <37 weeks 4% 37–42 weeks 2.5 [1.3–4.6]
1988–1994, <2500 g 3% 2500–4000 g 2.4 [1.2–4.7]
183 >4000 g 11% 1.3 [0.8–2.2]
cases<15 years
[13]
Germany, SGA 11% AGA 1.2 [0.7–2.1]
1992–1994, LGA 8% 1.6 [0.9–2.7]
160 cases
<14 years [14]
Italy, ≤37 weeks 15% 38–42 weeks 0.8 [0.5–1.3]
1998–2001, >42 weeks 5% 0.8 [0.3–2.2]
207 cases <2500 g 6% 2500–4000 g 0.6 [0.2–1.6]
<15 years [15]
>4000 g 8% 1.1 [0.6–2.0]
France, <37 weeks 7% 37–39 weeks 1.2 [0.8–1.9]
2003– ≥42 weeks 2% 2500–400 g 0.4 [0.1–1.3]
2004/2010– <2500 g 6% AGA 1.2 [0.9–1.7]
2011, ≥4000 g 9% 1.4 [0.9–2.2]
357 cases SGA 11% 1.4 [1.0–2.0]
<6 years [16] LGA 11% 1.5 [1.1–2.2]
1 Epidemiology 7
Table 1.3 (continued)

Study Exposure Prevalence Reference group OR [95% CI]
Record linkage studies
Norway, <37 weeks N/S 40–41 weeks 0.6 [0.2–2.0]
1967–2004, >42 weeks N/S 1.2 [0.7–2.0]
≤18 months <2500 g N/S 3000–3499 g 1.1 [0.3–3.7]
178 cases
≥4000 g N/S 1.8 [1.0–3.1]
<15 years [18]
>18 months <37 weeks N/S 40–41 weeks 0.7 [0.2–2.8]
>42 weeks N/S 1.6 [0.8–3.0]
≥4000 g N/S 3000–3499 g 0.9 [0.4–1.8]
US New-York <37 weeks 11% 37–42 weeks 0.4 [0.1–0.9]
state, 1976–1987 >42 weeks 12% 0.3 [0.1–0.7]
155 cases <2500 g 7% 3000–3499 0.9 [0.4–2.2]
<6 years [17] >4000 g 12% 1.2 [0.6–2.2]
US Minnesota <37 weeks 9% ≥37 weeks 1.0 [0.6–1.8]
state, <2500 g 7% 2500–4000 g 1.2 [0.6–2.3]
1976–2004, >4000 g 15% 1.1 [0.7–1.7]
155 cases
SGA 7% AGA 2.1 [1.1–4.0]
<14 years [19]
LGA 24% AGA 1.0 [0.7–1.5]
US California <37 weeks 12% 37–41 weeks 0.8 [0.6–1.2]
state, >42 weeks 11% 1.1 [0.8–1.5]
1988–1997, <2500 g 5% 2500–3999 g 1.0 [0.6–1.6]
508 cases
≥4000 g 12% 1.2 [0.9–1.7]
<5 years [21]
term/<2500 g 2% term/2500– 1.4 [0.6–3.0]
term/≥4000 g 10% 3999 g 1.2 [0.9–1.8]
US Washington <37 weeks 8% 37–42 weeks 0.6 [0.3–1.1]
state, >42 weeks 4% 1.2 [0.9–1.8]
1980–2004, <2500 g 5% 2500–3999 g 0.7 [0.4–1.5]
240 cases >4000 g 13% 1.2 [0.9–1.8]
<15 years [20]
SGA 9% AGA 0.9 [0.6–1.5]
LGA 10% 1.3 [0.8–1.9]
US New-York <38 weeks 14% 38–40 weeks 0.9 [0.7–1.2]
state, <2500 g 7% 2500–4500 g 1.5 [1.0–2.1]
1983–2001, >4500 g 2% 1.4 [0.7–2.5]
529 cases SGA 6% AGA 1.0 [0.5–1.9]
<15 years [22]
LGA 2% 1.1 [0.8–1.6]
%E proportion of exposed, SGA small for gestational age, LGA large for gestational age, AGA
appropriate for gestational age, N/S not stated
Regarding gestational age, no pattern of a positive or inverse association has

emerged, despite homogeneous definitions. By contrast, a slight positive relationship is
observed with high birth weight, with an estimated increase of 20% in a meta-analysis
(pooled OR 1.2 [95% CI 1.0–1.4]) [24]. The relation seems less clear in the studies
based on interview than in those based on birth certificates, which suggest that a bias in
maternal recall or in study sampling is possible. Only six studies [14, 16, 19–22] con-
sidered birth weight for gestational age, and they did not show clearer associations.
8 J. Clavel et al.
1.2.2 Maternal Vitamin or Folic Acid Intake Around Pregnancy
Periconceptional folic acid supplementation has been shown to reduce the risk of
neural tube defects by almost three-quarters [25]. It was therefore hypothesized that
the risk of neuroblastoma could also be reduced by maternal folic acid supplemen-
tation before conception and in the first trimester of pregnancy. Five studies [16, 23,
26–28] have investigated the association between vitamin/folic acid supplementa-
tion during pregnancy and neuroblastoma, four [16, 23, 26, 27] of which reporting
an inverse association with supplementation during preconception or during preg-
nancy, based on maternal interview.
1.2.3 Breastfeeding
Breastfeeding was reported to reduce risk of neuroblastoma in the COG North-

American study (0.6 [0.5–0.9]) [29] and in the French study (0.7 [0.5–1.0]) [16],
with no trend with increasing breastfeeding duration. Two other studies [24, 30]
based in less than 50 cases did not report significant associations.
1.2.4 Congenital Malformations
Nine studies which investigated the link between congenital malformations and neu-
roblastoma reported positive associations (Table 1.4). Detailed analyses are limited by
small numbers, given the rarity of both congenital malformations and neuroblasto-
mas. The associations with malformations, taken as a whole, are consistently reported
by interview-based studies and by studies based on birth certificates. Two studies sug-
gest that the association could be limited to children under 18 months [16, 18].
1.2.5 Parental Smoking and Alcohol Consumption
Overall, literature suggests that maternal tobacco smoking is associated with a

slight increase in risk of neuroblastoma (Table 1.5), as suggested by two recent
meta-analysis [43, 44]. Fewer studies report data on paternal smoking, and no con-
sistent pattern is observed to date. Findings on maternal alcohol drinking are also
heterogeneous.
1.2.6 Pesticides Exposures
Exposures to pesticides have been the most investigated environmental exposures,

and published papers are summarized in Table 1.6. Maternal occupational expo-
sures during pregnancy were addressed by five case–control studies, and all but one
1 Epidemiology 9
Table 1.4 Relative risk estimates for the association between congenital malformations and risk
of neuroblastoma
RR [95%
Study Exposure %E CI]
Interview-based case–control studies
US and Canada, Any malformation (ICD-10) 5.0% 2.5
1992–1994, [1.6–4.2]
538 cases <19 years [31] Major malformation 1.0% 7.5
[2.2–25.5]
Italy, 1998–2001, N/S 1.3% 4.9
207 cases <15 years [15] Major malformations (ICD-10) 2.5% [1.8–13.6]
France, 2003–2004 3.6
357 cases <6 years [16] [1.3–8.9]
<18 months 0.8
≥18 months [0.3–2.3]
Record linkage studies
England, Scotland, and Spina bifida (ICD-10) N/S 1.4 (ns)
Wales, 1971–1986, Cardiac septal defects (ICD-10) N/S 1.5 (ns)
1208 cases <15 years [32] Genitourinary (ICD-10) N/S 1.5 (ns)
Spine malformations (ICD-10) N/S 1.7 (ns)
Canada, 1977–1993 Any malformation (ICD-9) N/S p < 0.001
141 cases <15 years [33]
Norway, 1978–1997, N/S N/S 3.7
<18 months [1.7–8.0]
178 cases<15 years [18] N/S 0.7
≥18 months [0.1–4.7]
Australia, 1984–1993, Any malformation (ICD-9, British 2.5% 7.9
52 cases <15 years [34] Paediatric Association modification) [3.3–18.8]
US, Washington state, Any malformation 4.8% 2.1
1980–2004, Major malformations [1.3–3.4]
240 cases <20 years [20] 0.6% 6.7
[2.9–16.1]
US, California state, Nonchromosomal malformations 14% 1.0
1988–1997 <5 years [0.4–2.7]
508 cases <5 years [21] 5% 1.6
<1 year [0.8–3.3]
US Washington state, 1.9
1984–2013 [1.3–2.8]
327 cases <20 years [35]
%E proportion of exposed, CI confidence interval, N/S not specified, RR relative risk estimate
(odds ratio or standardized incidence ratio)
reported increased risk of neuroblastoma with farming or pesticides use. Two

cohorts and seven case–control studies investigated paternal exposure with incon-
sistent results, as summarized by a meta-analysis showing no association with neu-
roblastoma [53].
Increased risk of neuroblastoma was associated to self-reported use of household
pesticides before or after birth [13, 51, 52].
10
Table 1.5 Relative risk estimates for the association between maternal smoking and alcohol drinking during pregnancy and neuroblastoma
Maternal consumption during pregnancy
Study Cases and controls selection (ever/never)
Cases Controls Smoking Alcohol drinking Matched factors/Adjustments
Crude Crude
OR Adjusted OR Adjusted
Author, country, year [95% OR [95% [95% OR [95%
of case accrual Source n Source n CI]a CI] CI]a CI]
Data obtained by record linkage
Johnson et al., 2008 Cancer 155 Birth 8752 1.4 1.4 1.1 – Year of birth, sex
USA (1976–2004) [19] Registry Registry [0.9– [0.9–2.3] [0.4–
Minnesota 2.2] 3.5]
state
Chow et al., 2003 Cancer 240 Birth 2400 0.8 0.8 – – Year of birth, sex/gestational age,
USA (1980–1992) [20] Registry Registry [0.6– [0.6–1.2] birth weight, parental age, ethnicity,
Washington 1.2] maternal residence
state
McLaughlin et al., Cancer 529 Birth 12,010 – 1.0 – 1.2 Date of birth, sex
2009 Registry Records [0.7–1.3] [0.5–2.6]
USA (1985–2001) [22] New York
state
Stavrou et al., 2009 Cancer 122 Midwives 1,045,966 0.8 1.0 – – Children age and sex, maternal age,
Australia (1994–2005) Registry data [0.5– [0.6–1.7] birth weight, gestational age,
[36] New South collection 1.3] socioeconomics, maternal
Wales hypertension, gestational diabetes,
preeclampsia
Heck et al., 2016 Cancer 238 Birth 40,356 1.1 1.2 – – Year of birth/maternal ethnicity,
USA (2007–2013) [37] Registry certificates [0.5– [0.5–2.5] maternal education
California 2.4]
state
J. Clavel et al.
Data obtained by Interview
Kramer et al., 1987 Cancer 93 General 93 1.3 1.4 Date of birth, race, area code,
USA (1970–1979) [38] Registry population [0.8– [0.9–
Great 2.1] 2.2]
Delaware
valley
1 Epidemiology
Buck et al., 2001 Cancer 155 Birth 310 1.3 1.4 1.2 1.2 Year of birth, parity, maternal age,
USA (1976–1987) [17] Registry Registry [0.8– [0.9–2.1] [0.8– [0.8–1.9] smoking and alcohol consumption
New York 2.1] 1.9]
state
Sorahan et al., 1994 Cancer 93 Birth 93 – 1.0 – – Date of birth, sex
UK (1977–1981) [39] Registry Registry [0.8–1.3]
Schwartzbaum et al., Hospital 101 Hospital 690 – 1.9 – 0.7 Age, race, maternal age, social
1992 Cancer Cancer [1.1–3.2] [0.4–1.1] class, exposure to X-ray,
USA (1979–1986) [40] Registry Registry miscarriage, others (not specified)
Schuz et al., 2001 Cancer 183 Residents 1785 1.4 - 0.9 – Age, sex, year of birth/SES, degree
Germany (1988–1993) Registry database [1.0– [0.6– of urbanization
[13] 1.9] 1.3]
Pang et al., 2003 Cancer 188 Family 6987 – 0.9 – – Age, sex, parental age, deprivation
UK (1992–1994) [41] Registry Health [0.6–1.3] score
Services
database
Yang et al., 2000 Oncology 538 General 538 1.2 1.1 1.1 1.1 Date of birth/sex, race, maternal
USA (1992–1994) [42] Group population [0.9– [0.8–1.4] [0.9– [0.8–1.4] education, household income in the
1.6] 1.4] birth year
Parodi et al., 2014 Oncology 153 National 1044 1.4 1.2 – – Gender, date of birth, area of
Italy (1998–2001) [15] Group health [0.9– [0.7–2.1] residence/maternal age, and
service 2.2] maternal education
database
Rios et al., 2019 [43] Cancer 357 General 1783 1.3 1.3 0.9 1.0 Age, sex, maternal age, study of
Registry population [1.0– [0.9–1.7] [0.7– [0.8–1.4] origin
11
1.7] 1.1]
OR [95%CI] odds ratio and its 95% confidence interval
12 J. Clavel et al.
Table 1.6 Relative risk estimates for the association between parental pesticides exposures and
neuroblastoma
%E
Study Exposure Parent Period (controls) RR [95% CI]
Parental occupational exposures—cohorts
Norway, Field vegetable Any Any time N/S 2.5 [1.0–6.1]
1952–1991, farming parent Any time
27 cases [45] (agricultural
census)
US, 1993–1997, Farming Any N/S 1.3 [0.4–3.9]
3 cases [46] parent
Parental occupational exposures—case–control studies
US Greater Farming Any Pregnancy N/S 0.7 [0.1–5.8]
Philadelphia area, parent Preconception N/S 3.5 [0.7–35]
1970–1979, 104
cases [47]
US and Canada, Farming Maternal Any time N/S 2.2 [0.6–8.8]
1992–1996, Paternal Any time N/S 0.9 [0.4–1.8]
504 cases [48]
US New-York Field vegetable Maternal Pregnancy N/S 0.8 [0.2–3.2]
state, 1976–1987, farming Paternal Pregnancy N/S 1.0 [0.2–3.9]
183 cases [49] Insecticides use Maternal Pregnancy N/S 0.8 [0.2–3.2]
Paternal Pregnancy N/S 2.3 [1.4–3.7]
Germany, Farming Maternal After birth 3% 1.2 [0.4–3.7]
1988–1994, Any occupational Maternal Any time 1% 5.1 [1.1–23.4]
183 cases [13] use Paternal Any time 4% 1.8 [0.8–3.7]
Great Britain, Agriculture Paternal Pregnancy 2% 0.9 [0.6–1.3]
1962–1999, Agrochemical Paternal Pregnancy 3% 1.0 [0.7–1.4]
2920 cases [50] industry
Parental nonoccupational exposures—case–control studies
US and Canada, Household use Both Ever 31% 1.6 [1.0–2.3]
1992–1994, parents Preconception- 18% 1.3 [0.8–3.3]
390 cases [51] pregnancy
After birth 18% 1.4 [0.9–2.2]
Garden Both Ever 22% 1.7 [0.9–2.1]
parents Preconception- 13% 1.3 [0.8–2.0]
pregnancy
After birth 12% 1.8 [1.0–3.1]
Germany, Household insecticides use After birth 6% 1.8 [0.9–3.4]
1988–1993, Garden After birth 10% 0.9 [0.5–1.6]
183 cases [13] pesticides
France, 2003– Household use Pregnancy 30% 1.5 [1.0–2.1]
2004; 2010–2011 Insecticides use Pregnancy 28% 1.4 [0.9–2.0]
357 cases [52]
RR [95%CI] RR estimated (Standardized incidence ratio or odds ratio) and its 95% confidence
interval, N/S not stated
1 Epidemiology 13
1.2.7 Other Factors
Associations with maternal medication use, perinatal infections, parental occupa-

tional exposures to magnetic fields, hydrocarbons, or other chemicals [46, 48–50],
or residential exposure to air pollutants have been investigated reported, and no
consistent pattern has emerged yet [54, 55].
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Biology of Neuroblastoma
2
Gudrun Schleiermacher
2.1 Introduction
To date, the precise etiology of neuroblastoma is unknown, and unlike many adult
malignancies, environmental factors are not thought to play a major role, although
predisposing effects of prenatal exposures to potentially toxic substances warrant
further investigation. However, genetic factors, both at constitutional and somatic
levels, are thought to play a major role in neuroblastoma development [1].
2.2 Hereditary Genetic Factors
Several observations corroborate the hypothesis of a role of underlying hereditary

genetic factors in the etiology of neuroblastoma.
First, although rare and representing less than 1% of all cases [2], familial neu-
roblastomas have been described. Mutations of gain of function in the tyrosine
kinase domain of the ALK anaplastic lymphoma kinase gene have been detected in
the majority of familial cases [3, 4]. This is thought to be associated with an
autosomal-dominant pattern of inheritance with incomplete penetrance.
Second, neuroblastoma can appear in association with different clinical syn-
dromes. Neural crest-related developmental disorders associated with an increased
risk of developing neuroblastoma have been linked to inactivating mutations in the
PHOX2B gene, a major regulator of neural crest development, identified as the first
neuroblastoma predisposition mutation [5, 6]. While expansions of the second
G. Schleiermacher (*)
Recherche Translationnelle en Oncologie Pédiatrique, Institut Curie, Paris Cedex 05, France
SIREDO Département d’Oncologie Pédiatrique, Institut Curie, Paris Cedex 05, France
Inserm U 830, Institut Curie, Paris Cedex 05, France
e-mail: gudrun.schleiermacher@curie.net
© Springer Nature Switzerland AG 2020 17

S. Sarnacki, L. Pio (eds.), Neuroblastoma,
https://doi.org/10.1007/978-3-030-18396-7_2
18 G. Schleiermacher
polyalanine sequence of PHOX2B are mainly observed in patients with a curse of

Ondine (also called CCHS, Congenital Central Hypoventilation Syndrome) associ-
ated with a low risk of peripheral neuroblastic tumors, non-expansive mutations
with Hirschsprung’s disease are associated with a higher risk of developing neuro-
blastoma. Other associations between neuroblastic tumors and cancer susceptibility
syndromes include neurofibromatosis type 1 (NF1) [7], characterized by constitu-
tive activation of the RAS–MAPK pathway, as well as Noonan syndrome with
PTPN11 gene involvement.
Third, genome-wide association studies have shown that peripheral neuroblastic
tumors may occur in the context of underlying genetic factors, as it has been dem-
onstrated that different polymorphic alleles, localized at different genome loci,
influence oncogenesis [8–13]. Of a weak individual impact on the initiation of the
disease (with a relative risk of 1.5–2.0 compared to the global population), these
polymorphic alleles can cooperate in an individual patient to promote malignant
transformation during neurological development, and some genes targeted by these
polymorphic alleles play a role in the pathogenesis of neuroblastoma, including
BARD1, LMO1, DUSP12, DDX4, HACE1, and LIN28B. The polymorphic alleles
described show a correlation with high-risk or low-risk disease, indicating that
favorable and unfavorable forms of neuroblastoma may represent distinct entities in
terms of genetic events that initiate tumorigenesis.
In addition, rare cases with various aberrant constitutional karyotypes have been
described in patients with neuroblastoma, including constitutional copy-number
abnormalities, balanced and unbalanced translocations, and specific chromosomal
deletions, including deletions of chromosome 1p [14]. In total, there are probably as
yet undiscovered additional genes that predispose to neuroblastoma when they are
altered in the germline. It is important to note that, to date, there are no clinically
validated guidelines for determining who should be screened for germline muta-
tions, nor how to monitor patients or families with known susceptibility alleles.
2.2.1 Somatic Genetic Alterations
2.2.1.1 Copy-Number Alterations

With only 1–2% of neuroblastomas occurring in a familial context or predisposition,
over 98% of all cases occur sporadically. A large number of recurrent somatic genetic
alterations have been found in neuroblastoma, the most common being quantitative
genomic alterations with gains or losses in genetic material. These genetic abnor-
malities are related to distinct biological and clinical subgroups of the disease.
The amplification of the oncogene MYCN, located at chromosome 2p24.1, is
observed in about 25% of neuroblastomas and 40% of high-risk tumors [15]. It
remains one of the most important genetic alterations associated with advanced
stages of disease, with an aggressive phenotype and poor survival [1]. It is the first
genetic marker used in clinical practice for risk stratification and treatment adapta-
tion [16]. Closely associated with poor survival in patients with localized disease
and in infants, its prognostic impact in metastatic disease of older children with an
2 Biology of Neuroblastoma 19
overall poor outcome is less clear [16, 17]. At a cytogenetic level, amplification of
the MYCN oncogene occurs either as double-minute chromosomes (DM) or homo-
geneously staining regions (HSR), which contain between 10 and over 100 ectopic
copies of the MYCN oncogene. The oncogenic role of MYCN has been clearly dem-
onstrated as its ectopic expression in the neural crest is sufficient to drive neuroblas-
toma tumorigenesis in zebrafish and mice models [18]. Its oncogenic role is based
on an enhancement of the expression of genes involved in cell proliferation, and on
the repression of genes involved in differentiation and apoptosis [19].
Other recurrent amplifications concern the ALK gene on chromosome 2p23, as
well as amplicons of chromosome 12q13–14 encompassing, among others, the
MDM2 and CDK4 genes [20]. Recent data indicate that NB with focal amplifica-
tions other than MYCN might present with atypical clinical features and a poorer
outcome [21].
Other recurrent structural alterations recurrently observed in neuroblastoma con-
cern segmental chromosome alterations (SCA) corresponding to unbalanced chro-
mosome translocations, including deletions of chromosome arms 1p, 3p, 4p, and
11q, and gains of 1q, 2p, or 17q. Although several recurrently altered chromosome
regions have been identified, chromosome breakpoints are not recurrent but lie scat-
tered over wide genomic regions. Deletion of 1p36 is observed in 20–35% of cases
and is associated with poor survival in multivariate analyses as well as with aggres-
sive disease markers [22, 23]. Deletions of 11q in a consensus region at 11q23 occur
in approximately 40% of cases and are inversely correlated with MYCN amplifica-
tion, identifying a molecularly distinct high-risk patient subset, characterized by
advanced stage, older age, as well as a higher genomic instability with a higher
number of chromosome breakpoints [24, 25]. Gains of chromosome 17q21-qter
represent the most frequent genetic alteration in neuroblastoma, occurring in 70%
of tumors. Numerous studies have reported that 17q gain is significantly associated
with advanced stage of disease, increased patient age, MYCN amplification, as well
as other unfavorable genetic parameters [26].
Although intense decade-long research has focused on the identification of hypo-
thetical tumor-suppressor genes or oncogenes in recurrently altered regions of chro-
mosome loss or gain, the smallest regions of overlap remain quite extensive and to
date do not point to single-gene candidates as tumor suppressors or oncogenes,
suggesting that an overall imbalance of copy-number regions is of importance in
neuroblastoma oncogenesis.
Although the individual segmental chromosome alterations have been shown to
correlate with outcome, importantly, the overall genomic profile has been shown to
be of prognostic impact in neuroblastoma [27–30]. Whereas an overall genomic
copy-number profile characterized by numerical chromosome alterations, consist-
ing of gains or losses of whole chromosomes, is associated with a favorable out-
come, segmental chromosome alterations of any chromosome region, without or
with numerical chromosome alterations, are associated with advanced stage of dis-
ease, with an increased age at diagnosis and, importantly, a higher risk of relapse in
multivariate analyses [27, 28, 31]. In addition to the determination of MYCN ampli-
fications status, the overall genomic copy-number profile determined by array
comparative genomic hybridization (CGH) or single nucleotide polymorphism

(SNP) array is now considered part of routine work up in particular in low- and
intermediate-risk neuroblastoma and might be used for treatment stratification
within prospective clinical protocols [1].
Higher-resolution copy-number analyses have also revealed smaller recurrent
interstitial events. Indeed, SNP arrays have identified alterations on chromosome
9p, with homo- or hemizygous deletions encompassing the CDKN2A gene [32].
Other sporadic copy-number alterations include focal TERT gains [33] and micro-
deletions encompassing the PTPRD gene [34].
More complex rearrangements resulting from chromothripsis, corresponding to
massive genomic rearrangements acquired in a single catastrophic event, have been
described in neuroblastoma, but their association with other genomic and clinical
subtypes remains to be determined [35, 36].
2.2.1.2 Single-Gene Mutations

Recent next-generation sequencing approaches have indicated that most neuroblas-
tomas harbor only few mutations, with an average of 10–20 predicted non-
synonymous variations in coding regions per genome, indicating an exonic mutation
frequency of 0.2–0.4 per Mb. [35, 37–39] The frequency of somatic events strongly
correlates with tumor stage, higher-stage tumors harboring a higher number of
mutations.
The most frequent recurrent somatic mutation in neuroblastoma concerns the
gene ALK (anaplastic lymphoma kinase), with mutations activating the tyrosine
kinase domain in approximately 10% of all cases at diagnosis. [3, 4] The somatic
ALK-1174 mutation appears to contribute to a more aggressive phenotype, but
unlike ALK-1275 mutations, these specific mutations are not found in familial neu-
roblastoma, suggesting that they are not tolerated in the germline [40, 41]. The
oncogenic role of activating ALK mutations in neuroblastoma has been demon-
strated in vitro and in vivo in both zebrafish and mouse models, with coexpression
of ALK-F1174L and MYCN producing a synergistic effect for neuroblastoma
tumorigenesis in mice. New-generation small-molecule inhibitors targeting the acti-
vated kinase domain of ALK are now available, making this a promising target for
molecular therapy, possibly in combination therapies, but still requiring more spe-
cific development [40, 42, 43].
Other recurrent mutations in neuroblastoma target distinct cellular pathways and
include PTPN11 mutations (in 3% of cases), as well as genes involved in cytoskele-
ton maintenance, neuritogenesis, and other regulators of the RAC/Rho pathway [35].
Interestingly, genes involved in chromatin remodeling have been found to be
targeted in a significant number of cases, either by mutations or by structural varia-
tions, including mutations in the ARID1A/ARID1B genes [38]. Somatic alterations
of ATRX, consisting either of mutations or small interstitial deletions, are associ-
ated with an increase in telomere length and with an absence of the ATRX protein
in the nucleus. ATRX alterations appear to be more frequent in older children and
occur in mutually exclusive fashion with MYCN amplifications [39]. ATRX muta-
tions are associated with activation of a telomere maintenance mechanism termed
alternate lengthening of telomeres (ALT), which may be associated with primary

chemotherapy resistance.
Recurrent genomic rearrangements of the promoter region of the telomerase
reverse transcriptase (TERT) gene on chromosome 5p15.33 have been described in
>10% of neuroblastoma cases, with structural rearrangements of TERT resulting
from chromothripsis in some cases [44, 45]. These rearrangements, which are asso-
ciated with increased TERT expression, target regions immediately up- and down-
stream of TERT, and position the TERT coding sequence to strong enhancer
elements, resulting in massive chromatin remodeling and DNA methylation of the
affected region. [44] Occurring in mutually exclusive fashion with MYCN amplifi-
cation and ATRX mutations, these rearrangements define a further subgroup of high-
risk disease, with TERT rearrangements (23%), ATRX deletions (11%), and MYCN
amplifications (37%) identifying three almost non-overlapping groups of high-stage
neuroblastoma, each associated with very poor prognosis.
Thus, a large number of high-risk neuroblastomas are affected by genetic altera-
tions of either MYCN, TERT, or ATRX, all of which converge to an activation of
telomere-lengthening mechanisms either by direct activation or by ALT, leading to
a capacity of near-infinite cell proliferation. [46] Advances in the development of
inhibitors of these pathways and their evaluation in clinical trials will lead to new
treatment opportunities.
Future studies will determine if the association between these major players in
neuroblastoma oncogenesis with distinct genetic profiles and mutational patterns
might serve for the definition of different risk groups in particular in high-risk
neuroblastoma.
Overall, large-scale sequencing efforts have highlighted distinct mutational sig-
natures which are thought to reflect distinct biochemical cellular processes [47]. In
neuroblastoma, in some cases a predominance of C > T transitions, termed muta-
tional signature 1, are observed, with an association with age. Other mutational
signatures observed in neuroblastoma, although rarer, concern the canonical double-
stranded break signature linked to mutations in BRCA1 or BRCA2 or to a
“BRCAness” phenotype [48]. Altogether, these studies underline the heterogeneity
of somatic genetic alterations in neuroblastoma and highlight the importance to
pursue efforts of molecular characterization.
2.2.1.3 Expression Profiles

In addition to genetic changes, neuroblastoma can also be characterized by specific
expression profiles. Indeed, to date, a large number of studies have focused on the
analysis of differential expression patterns in NB, seeking to identify expression
patterns that might be enable to distinguish patients with different clinical courses
and thus define different prognostic groups in high-risk disease, and to potentially
identify new therapeutic targets.
Thus, different expression signatures, based on 144-gene or 59-gene signatures,
reliably distinguished patients with distinct clinical courses, with the strongest dif-
ference observed in non-high-risk disease [49, 50]. Using real-time PCR expression
data, an expression signature based on only three genes (CHD5, PAFAH1B1, and
NME1) has been able to discriminate patients with different outcomes [51]. Among
high-risk patients, an expression profile based on 55 genes defined patient popula-
tions with divergent outcome [52]. Differential expression signature depending on
MYCN has led to a definition of a 157-gene signature which identified NB patients
with poor prognosis independent of the genomic MYCN status, those without MYCN
amplification presenting stabilization of MYCN at the protein level [53].
More recently, based on the hypothesis that tumor-associated inflammatory cells
might contribute to the differences in age-dependent outcome of patients with meta-
static NB, expression of genes representing tumor-associated macrophages, such as
CD33/CD16/IL6R/IL10/FCGR3, contributed to a novel 14-gene tumor classifica-
tion score. Progression-free survival was 47% versus 12% for patients with a low-
versus a high-risk score, indicating that interactions between tumor and inflammatory
cells may contribute to an aggressive metastatic NB phenotype [54].
In addition to messenger RNA, expression levels of non-coding RNAs are also
highly variable. Micro-RNAs function as regulators of gene expression at the post-
transcriptional level in diverse cellular processes and constitute the most widely
studied non-coding RNA molecules in NB. MYCN modulates the expression of sev-
eral classes of non-coding RNAs, especially some micro-RNAs, and it can also
regulate the expression of long non-coding RNAs such as T-UCRs (Transcribed
UltraConserved Regions) and non-coding RNA, whereas other long non-coding
RNAs remain to be characterized in NB. The landscape of T-UCRs in NB has been
studied recently and has revealed a correlation with the MYCN status, and prelimi-
nary studies have suggested that T-UCR-based expression signatures might distin-
guish short-from long-term survivors in high risk NB [55].
The miRNA expression pattern can also be used to classify NB patients accord-
ing to survival [56, 57]. An advantage of the study of miRNA rather than mRNA
expression signatures is linked to the greatest stability of miRNAs, and thus to an
analytical feasibility even with formalin-fixed, paraffin-embedded (FFPE) samples
as opposed to frozen samples [57]. The miRNA expression pattern can also be used
to classify NB patients according to survival [56, 57].
The paucity of recurrent genetic mutations as compared to adult tumors indicates
that additional mechanisms such as epigenetic alterations may play an important
role in the molecular pathogenesis of these developmental tumors. Alterations in
DNA methylation represent one of the most common molecular events in neoplasia,
and CpG-island hypermethylation of gene promoters is a frequent mechanism for
functional inactivation of relevant tumor-associated genes in neuroblastoma.
Promoter methylation patterns which are associated with patient subgroups and dis-
tinct clinical features have been identified [58]. Further studies are now necessary to
determine whether these genome-wide methylation patterns correlate with outcome
and other prognostic molecular markers in NB patients.
Taken together, to date, many studies have demonstrated the feasibility of expres-
sion profiling of mRNA, miRNA, other non-coding RNAs, or epigenetic modifiers
in order to determine different prognostic subgroups among NB patients. However,
there is little, if any, overlap between the genes of the different signatures rendering
cross-study comparisons unfeasible. Furthermore, although most expression signa-
tures clearly distinguish prognostic groups in the overall population, differences in
survival among high-risk patients are frequently not very marked. The routine setup
of real-time determination of expression profiles in a prospective clinical trial set-
ting, and their interpretation, remains a clear challenge.
2.2.1.4 Spatial and Temporal Heterogeneity

Neuroblastoma presents important spatial and temporal heterogeneity. Spatial het-
erogeneity has been recorded for several recurrent somatic genetic alterations in
neuroblastoma. Indeed, MYCN alterations might occur only in a subset of neuro-
blastic cells of a given tumor [59]. Segmental chromosome alterations might also
vary between different neuroblastic cell populations [60, 61]. Furthermore, muta-
tions can also be observed at a heterogeneous level. In some tumors, low-level
mutated allele fractions for ALK driver mutations have been observed [62].
In neuroblastoma, temporal heterogeneity can also occur. Indeed, genetic altera-
tions may evolve over time and clonal evolution is common, leading to the acquisi-
tion of somatic alterations in known oncogenic pathways, some of which may be
targeted. ALK-activating mutations, in some instance present in a minor subclone at
diagnosis, might emerge at relapse [63]. Furthermore, activation of the MAPK path-
way and other signaling pathways for epithelial–mesenchymal transition (EMT)
processes may appear during a relapse and represent promising targets for targeted
molecular treatment approaches [64, 65]. In total, spatial and temporal genetic het-
erogeneity plays an important role in neuroblastoma.
However, multi-site tumor biopsies, or sequential biopsies from the same tumor,
can only rarely be realized, and recently liquid biopsies have emerged as a very
promising tool to explore somatic genetic alterations with regards to both spatial
and temporal heterogeneity. Indeed, circulating tumor DNA, a fraction of cell-free
DNA, can readily be extracted from plasma of neuroblastoma patients. This can
serve for the detection of MYCN amplification [66]. Copy-number alterations or
mutations such as ALK can also be detected in ctDNA. [67–69] More recently
application of whole-exome sequencing techniques to sequential ctDNA samples
from NB patients has provided further evidence of the importance of clonal evolu-
tion in the progression of neuroblastoma, enabling the description of resistant clones
emerging at the time of relapse [70].
Altogether, as neuroblastoma is in general associated with a low mutational bur-
den and only few recurrently occurring mutations, it might be considered a copy-
number disease, with large chromosome segments contributing to oncogenesis by
gene dosage effects. Further ongoing efforts will enable to determine whether epi-
genetic changes also play a role in neuroblastoma oncogenesis.
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In speaking thus of the midshipmen’s birth, and of their occasional
ruggedness of manners, I should be doing wrong to leave an
impression that they were a mere lawless set of harumscarum
scamps. Quite the contrary; for we had a code of laws for our
government, which, for precision and distinctness of purpose, might
have rivalled many of those promulgated by the newest-born states
of the world, in these days of political parturition. I observe, that
young countries, like young people, whether in a midshipman’s
mess, or any where else, delight in the indulgence of the fond and
false idea, that it is easy to regulate the fluctuations of human nature
exactly as they please, by the mere force of written constitutions.
They always ‘remember to forget,’ that institutions, to be in the
smallest degree effective in practice, must be made to fit the existing
state of society, and that society cannot possibly be made to fit them.
They almost all run away, however, with the vainest of vain notions,
that established habits, old prejudices, with all the other fixed and
peculiar circumstances of the time and place in which they find
themselves, have become, of a sudden, so pliable, that they can be
essentially and speedily modified by artificial legislation alone! On
this fallacious principle we framed a set of regulations for our mess,
of which I recollect only one, giving, I admit, rather a queer idea of
the state of things in our maritime world. It ran thus:—“If any member
of the larboard mess shall so far forget the manners of a gentleman
as to give the lie direct to one of his messmates, he shall be fined
one dollar.”
This fine, it must be observed, was intended purely as a
propitiation to the offended dignity of the mess, and was quite
independent of the personal arrangements which, on such
occasions, generally took place in the cock-pit outside. These battles
royal were fought across a chest,—I don’t mean with pistols, but with
good honest fisty-cuffs. The only difficulty attending this method of
settling such matters consisted in the shifts to which the parties were
compelled to resort, to conceal the black eyes which, in most cases,
were the result of these single combats. It would, of course, have
been quite incorrect in the commanding officer to have overlooked
such proceedings—even supposing the parties to retain a sufficiency
of optics to do their duty. The usual resource was to trust to the
good-nature of the surgeon, who put the high contending parties on
the sick list, and wrote against their names “Contusion;” an entry he
might certainly make with a safe conscience!
This innocent way of settling disputes was all very well, so long as
the mids were really and truly boys; but there came, in process of
time, a plaguy awkward age, when they began to fancy themselves
men, and when they were very apt to take it into their heads that, on
such occasions as that just alluded to, their dignity, as officers and
gentlemen, would be compromised by beating one another about the
face and eyes across a chest, and otherwise contusing one another,
according to the most approved fashion of the cock-pit. Youths, at
this intermediate age, are called Hobbledehoys, that is, neither man
nor boy. And as powder and ball act with equal efficacy against
these high-spirited fellows as against men of more experience, fatal
duels do sometimes take place even amongst midshipmen. I was
once present at a very foolish affair of this kind, which, though it
happily ended in smoke, was so exceedingly irregular in all its parts,
that, had any one fallen, the whole party concerned would most
probably have been hanged!
A dispute arose between three of these young men, in the course
of which, terms were bandied about, leaving a reproach such that
only the ordeal of a duel, it was thought, could wipe out. It was late in
the day when this quarrel took place; but as there was still light
enough left to fire a shot, the party went on deck, and quietly asked
leave to go on shore for a walk. I happened to be the only person in
the birth at the time who was not engaged in the squabble, and so
was pressed into the service of the disputants to act as second.
There would have been nothing very absurd in all this, had there
been another second besides me, or had there existed only one
quarrel to settle—but between the three youths there were two
distinct disputes!
One of these lads, whom we shall call Mr. A, had first to fight with
Mr. B, while Mr. C was second to Mr. B; and then Mr. A, having
disposed of Mr. B, either by putting him out of the world, or by
adjusting the matter by apologies, was to commence a fresh battle
with Mr. C, who, it will be observed, had been second to his former
antagonist, Mr. B! The contingency of Mr. A himself being put hors
de combat appears not to have been contemplated; but the strong
personal interest which Mr. C (the second to Mr. A’s first antagonist)
had in giving the affair a fatal turn, would have been the ticklish point
for our poor necks, in a court of justice, had Mr. A fallen. Poor fellow!
he was afterwards killed in action.
More by good luck than good management, neither of the first
shots took effect. At this stage of the affair, I began to perceive the
excessive absurdity of the whole transaction, and the danger of the
gallows, to which we were all exposing ourselves. I therefore
vehemently urged upon the parties the propriety of staying further
proceedings. These suggestions were fortunately strengthened by
the arrival of a corporal’s guard of armed marines from the ship,
under the orders of an officer, who was directed to arrest the whole
party. There was at first a ludicrous shew of actual resistance to this
detachment; but, after some words, the affair terminated, and the
disputants walked off the field arm in arm, the best friends in the
world!
CHAPTER VIII.
MAST-HEADING A YOUNG GENTLEMAN.
On the 8th of January, 1804, we sailed from Halifax, and, after a long
and tedious passage, arrived at Bermuda. The transition from the
intense frost of a Nova Scotian winter, during which the mercury was
generally below zero, to a temperature of 70° or 80°, was
exceedingly agreeable to those who had constitutions to stand the
sudden rise of more than half a hundred degrees of the
thermometer. After a few days’ stay at Bermuda, we set off for the
United States, where we were again frozen, almost as much as we
had been at Halifax. The first land we made was that of Virginia; but
owing to calms, and light foul winds, we failed in getting to Norfolk in
the Chesapeak, and therefore bore up for New York, which we
reached on the 19th of February, and there anchored about seven
miles from that beautiful city.
It was not thought right to let any of us young folks visit the shore
alone; but I was fortunate in being invited to accompany one of the
officers. To the friendship of this most excellent person, at the
periods of most need, I feel so much more indebted than I can
venture to express without indelicacy, that I shall say nothing of the
gratitude I have so long borne him in return. Perhaps, indeed, the
best, as being the most practical, repayment we can ever make for
such attentions is, to turn them over, again and again, to some other
person similarly circumstanced with ourselves at those early periods.
This would be acting in the spirit with which Dr. Franklin tells us he
used to lend money, as he never gave it away without requiring from
the person receiving such assistance, a promise to repay the loan,
not to himself, but to transfer it, when times improved, to some one
else in distress, who would enter into the same sort of engagement
to circulate the charity. On this principle, I have several times, in the
course of my professional life, rather surprised young middies by
giving them exactly such a lift as I myself received at New York—
shewing them strange places, and introducing them to the
inhabitants, in the way my kind friend adopted towards me. These
boys may perhaps have fancied it was owing to their own uncommon
merit that they were so noticed; while all the time I may have merely
been relieving my own conscience, and paying off, by indirect
instalments, a portion of that debt of gratitude which, in spite of these
disbursements, I find only increases in proportion as my knowledge
of the world gives me the means of appreciating its value.
That it is the time and manner of doing a kindness which constitute
its chief merit, as a matter of feeling at least, is quite true; and the
grand secret of this delicate art appears to consist in obliging people
just at the moments, and, as nearly as possible, in the particular way,
in which they themselves wish the favour to be done. However
perverse their tastes may be, and often, perhaps, because they are
perverse, people do not like even to have favours thrust upon them.
But it was my good fortune on this, and many other occasions in life,
early and late, to fall in with friends who always contrived to nick the
right moments to a hair’s-breadth. Accordingly, one morning, I
received an invitation to accompany my generous friend, one of the
lieutenants, to New York, and I felt, as he spoke, a bound of joy, the
bare recollection of which makes my pulse beat ten strokes per
minute quicker, at the distance of a good quarter of a century!
It would not be fair to the subject, nor indeed quite so to myself, to
transcribe from a very boyish journal an account of this visit to New
York. The inadequate expression of that period, compared with the
vivid recollection of what I then felt, shews, well enough, the want of
power which belongs to inexperience. Very fortunately, however, the
faculty of enjoying is sooner acquired than the difficult art of
describing. Yet even this useful and apparently simple science of
making the most of all that turns up, requires a longer apprenticeship
of good fortune than most people are aware of.
In the midst of snow and wind, we made out a very comfortless
passage to New York; and, after some trouble in hunting for
lodgings, we were well pleased to find ourselves snugly stowed
away in a capital boarding house in Greenwich Street. We there
found a large party at tea before a blazing wood fire, which was
instantly piled with fresh logs for the strangers, and the best seats
relinquished for them, according to the invariable practice of that
hospitable country.
If our hostess be still alive, I hope she will not repent of having
bestowed her obliging attentions on one who, so many years
afterwards, made himself, he fears, less popular in her land, than he
could wish to be amongst a people to whom he owes so much, and
for whom he really feels so much kindness. He still anxiously hopes,
however, they will believe him when he declares, that, having said in
his recent publication no more than what he conceived was due to
strict truth, and to the integrity of history, as far as his observations
and opinions went, he still feels, as he always has, and ever must
continue to feel towards America, the heartiest good-will.
The Americans are perpetually repeating, that the foundation-
stone of their liberty is fixed on the doctrine, that every man is free to
form his own opinions, and to promulgate them in candour and in
moderation. Is it meant that a foreigner is excluded from these
privileges? If not, may I ask, in what respect have I passed these
limitations? The Americans have surely no fair right to be offended
because my views differ from theirs; and yet, I am told, I have been
rudely enough handled by the press of that country. If my motives
are distrusted, I can only say I am sorely belied; if I am mistaken,
regret at my political blindness were surely more dignified than anger
on the part of those with whom I differ; and if it shall chance that I am
in the right, the best confirmation of the correctness of my views, in
the opinion of indifferent persons, will perhaps be found in the
soreness of those who wince when the truth is spoken.
Yet, after all, few things would give me more real pleasure than to
know that my friends across the water would consent to take me at
my word; and, considering what I have said about them as so much
public matter—which it truly is—agree to reckon me in my absence,
as they always did when I was amongst them—and I am sure they
would count me if I went back again—as a private friend. I differed
with them in politics, and I differ with them now as much as ever; but
I sincerely wish them happiness individually; and as a nation, I shall
rejoice if they prosper. As the Persians write, “What can I say more?”
And I only hope these few words may help to make my peace with
people who justly pride themselves on bearing no malice. As for
myself, I have no peace to make; for I have studiously avoided
reading any of the American criticisms on my book, in order that the
kindly feelings I have ever entertained towards that country should
not be ruffled. By this abstinence, I may have lost some information,
and perhaps missed many opportunities of correcting erroneous
impressions. But I set so much store by the pleasing recollection of
the journey itself, and of the hospitality with which my family were
every where received, that, whether it be right, or whether it be
wrong, I cannot bring myself to read any thing which might disturb
these agreeable associations. So let us part in peace! or rather, let
us meet again in cordial communication; and if this little work shall
find its way across the Atlantic, I hope it will be read there without
reference to any thing that has passed between us; or, at all events,
with reference only to those parts of our former intercourse which are
satisfactory to all parties.
After leaving the American coast, we stood once more across the
gulf stream for Bermuda. Here I find the first trace of a regular
journal, containing a few of those characteristic touches which, when
we are sure of their being actually made on the spot, however
carelessly, carry with them an easy, familiar kind of interest, that
rarely belongs to the efforts of memory alone. It is, indeed, very
curious how much the smallest memorandums sometimes serve to
lighten up apparently forgotten trains of thought, and to bring vividly
before the imagination scenes long past, and to recall turns of
expression, and even the very look with which these expressions
were uttered, though every circumstance connected with them may
have slept in the mind for a long course of years.
It is, I believe, one of the numerous theories on the mysterious
subject of dreams, that they are merely trains of recollections,
touched in some way we know not of, and influenced by various
causes over which we have no sort of control; and that, although
they are very strangely jumbled and combined, they always relate,
so exclusively, either to past events, or to past thoughts, that no
ideas strictly new ever enter our minds in sleep.
Be this true or false, I find that, on reading over the scanty notes
above alluded to, written at Bermuda more than six-and-twenty years
ago, I am made conscious of a feeling a good deal akin to that which
belongs to dreaming. Many objects long forgotten, are brought back
to my thoughts with perfect distinctness; and these, again, suggest
others, more or less distinctly, of which I possess no written record.
At times a whole crowd of these recollections stand forward, almost
as palpably as if they had occurred yesterday. I hear the well-known
voices of my old messmates—see their long-forgotten faces—and
can mark, in my memory’s eye, their very gait, and many minute and
peculiar habits. In the next minute, however, all this is so much
clouded over, that by no effort of the imagination, assisted even by
the journal, can I bring back the picture as it stood before me only a
moment before. It sometimes also happens in this curious
retrospect, that a strange confusion of dates and circumstances
takes place, with a vague remembrance of hopes, and fears, and
wishes, painful anticipations, and bitter passing thoughts, all long
since gone. But these day dreams of the past sometimes come
rushing back on the fancy, all at once, in so confused a manner, that
they look exceedingly like what is often experienced in sleep. Is
there, in fact, any other difference, except that, in the case of
slumber, we have no control over this intellectual experiment, and, in
the other, we have the power of varying it at pleasure? When awake
we can steer the mental vessel with more or less precision—when
asleep our rudder is carried away, and we must drift about at the
capricious bidding of our senses, over a confused sea of
recollections.
It may be asked, what is the use of working out these
speculations? To which I would answer, that it may often be highly
useful, in the practice of life, for people to trace their thoughts back,
in order to see what have been the causes, as well as the effects, of
their former resolutions. It is not only interesting, but may be very
important, to observe how far determinations of a virtuous nature
had an effectual influence in fortifying us against the soft
insinuations, or the rude assaults of temptation; or how materially
any original defect or subsequent omission in such resolutions may
have brought us under the cutting lash of self-reproach.
It would probably be very difficult, if not impossible, for any person
to lay open his own case so completely to the view of others, that the
rest of the world should be enabled to profit, as he himself, if he
chooses, may do, by his past experience in these delicate matters. I
shall hardly attempt such a task, however; but shall content myself
with saying, that, on now looking back to those days, I can, in many
instances, lay my hand upon the very hour, the very incident, and the
very thought and feeling, which have given a decided direction to
many very material actions of the intervening period. In some cases,
the grievous anguish of remorse has engraved the lesson so deeply
on the memory, that it shews like an open wound still. In others, it
has left only a cicatrice, to mark where there has been suffering. But
even these, like the analogous case of bodily injuries, are liable to
give their twitches as the seasons vary.
It is far pleasanter, however, and a still more profitable habit, I am
quite sure, to store up agreeable images of the past, with a view to
present and future improvement, as well as enjoyment, than to
harass the thoughts too much by the contemplation of opportunities
lost, or of faculties neglected or misused. Of this cheerful kind of
retrospect, every person of right thoughts must have an abundant
store. For, let the croakers say what they please, ‘this brave world’ is
exceedingly fertile in sources of pleasure to those whose principles
are sound, and who, at all times and seasons, are under the
wholesome consciousness, that while, without higher aid, they can
essentially do nothing, there will certainly be no such assistance lent
them, unless they themselves, to use a nautical phrase, ‘bend their
backs like seamen to the oar,’ and leave nothing untried to double
the Cape of their own life and fortunes. It is in this vigorous and
sustained exertion that most persons fail—this ‘attention suivie,’ as
the French call it, which, as it implies the absence of self-distrust,
gives, generally, the surest earnest of success.
It has sometimes struck me as not a little curious, that, while we
have such unbounded faith in the constancy of the moon’s motions,
and rest with such confidence on the accuracy of our charts and
books, as to sail our ships, in the darkest nights, over seas we have
never before traversed; yet that, in the moral navigation of our lives,
we should hesitate in following principles infinitely more important,
and in which we ought to have a faith at least as undoubting. The old
analogy, indeed, between the storms of the ocean, and those of our
existence, holds good throughout this comparison; for the half-
instructed navigator, who knows not how to rely on his chart and
compass, or who has formed no solid faith in the correctness of the
guides to whom he ought to trust his ship, has no more chance of
making a good passage across the wide seas, than he whose petty
faith is bounded by his own narrow views and powers, is likely to be
successful in the great voyage of life.
There is a term in use at sea called ‘backing and filling,’ which
consists at one moment in bracing the yards so that the wind shall
catch the sails in reverse, and, by bringing them against the masts,
drive the ship stern-foremost; and then, after she has gone far
enough in that direction, in bracing up the yards so that the sails may
be filled, and the ship again gather headway. This manœuvre is
practised in rivers when the wind is foul, but the tide favourable, and
the width of the stream too small to admit of working the vessel
regularly, by making tacks across. From thus alternately approaching
to the bank and receding from it, an appearance of indecision, or
rather of an unwillingness to come too near the ground, is produced,
and thence the term is used to express, figuratively, that method of
speaking where reluctance is shewn to come too near the abrupt
points of the subject, which yet must be approached if any good is to
be done. I confess, accordingly, that, just now, I have been ‘backing
and filling’ with my topic, and have preferred this indirect method of
suggesting to my young friends the fitting motives to action, rather
than venturing to lecture them in formal terms. The paths to honour,
indeed, every man must trace out for himself; but the discovery will
certainly be all the easier if he knows the direction in which they lie.
The following brief specimen of a midshipman’s journal will shew,
as well as a whole volume could do, the sort of stuff of which such
documents are made. The great fault, indeed, of almost all journals
consists in their being left, like Chinese paintings, without shading or
relief, and in being drawn with such a barbarous perspective, that
every thing appears to lie in one plane, in the front of the picture.
“Bermuda, Sunday, April 22.
“Wind south. Last night I had the first watch. Turned out
this morning at seven bells. Breakfasted on a roll and
some jelly. Wind blowing pretty hard at south. Struck lower
yards and top-gallant masts. After breakfast read one or
two tales of the Genii. Dressed for muster, and at six bells
beat to divisions. I asked leave to go on shore to dine with
Capt. O’Hara, but was refused. So I dined upon the Old
thing—salt junk and dough. The captain landed in the
pinnace. Employed myself most of the afternoon in
reading Plutarch’s Lives. Had coffee at four o’clock.
Blowing harder than ever, and raining very much. Read
the Bible till six; then went on deck. At nine went to bed.
Turned out at four in the morning.
“Monday, 23d April.—Made the signal for sailing. At
noon, the same old dinner—salt horse! The two pilots,
Jacob and Jamie, came on board. Employed getting in the
Admiral’s stock.”
These two names, Jacob and Jamie, will recall to people who
knew Bermuda in those days many an association connected with
that interesting island. They were two negroes, pilots to the men-of-
war, who, in turn, took the ships out and in. Their wives, no less
black and polished than themselves, were the chief laundresses of
our fleet; while at their cedar-built houses on shore, we often
procured such indifferent meals as the narrow means of the place
allowed. I only remember that our dinner, nine times in ten, consisted
of ham and eggs. I forget whether or not these men were slaves; I
think not: they were, at all events, extremely good-natured fellows,
and always very kind and obliging to the midshipmen, particularly to
those who busied themselves in making collections of shells and
corallines, the staple curiosities of the spot.
It is needless to quote any more from the exact words of this
matter-of-fact journal. I find it recorded, however, that next morning a
boat came to us from the Boston, a frigate lying near the Leander.
The captain of that ship was then, and is now, one of my kindest and
steadiest friends. And right well, indeed, did he know how to confer a
favour at the fitting season. The boat contained one of the most
acceptable presents, I will answer for it, that ever was made to
mortal—it was truly manna to starved people—being no less than a
famous fat goose, a huge leg of pork, and a bag of potatoes!
Such a present at any other time and place would have been
ludicrous; but at Bermuda, where we had been starving and growling
for many months without a fresh meal—it was to us hungry, salt-fed
boys, the ‘summum bonum’ of human happiness.
Next day, after breakfast, the barge was sent with one of the
lieutenants for the Admiral, who came on board at eleven o’clock.
But while his excellency was entering the ship on one side, I quitted
my appointed station on the other, and, without leave, slipped out of
one of the main-deck ports into the pilot-boat, to secure some conch
shells and corals I had bespoken, and wished to carry from Bermuda
to my friends at Halifax. Having made my purchases, in the utmost
haste and trepidation, I was retreating again to my post, when, as my
ill stars would have it, the first lieutenant looked over the gangway.
He saw at a glance what I was about; and, calling me up, sent me as
a punishment to the mast head for being off deck when the Admiral
was coming on board. As I had succeeded in getting hold of my
shells, however, and some lumps of coral, I made myself as
comfortable as possible in my elevated position; and upon the whole
rather enjoyed it, as a piece of fun.
We then hove up the anchor, and as we made sail through the
passage, I could not only distinguish, from the mast head, the
beautifully coloured reefs under water, but trace with perfect ease all
the different channels between them, through which we had to
thread our winding, and apparently dangerous, course. As the ship
passed, the fort saluted the flag with twelve guns, which were
returned with a like number; after which we shaped our course for
Norfolk, in Virginia.
So far all was well. I sat enjoying the view, in one of the finest days
that ever was seen. But it almost makes me hungry now, at this
distance of time, to tell what followed.
From the main-top-mast cross-trees, on which I was perched for
my misdeeds, I had the cruel mortification of seeing my own
beautiful roast goose pass along the main-deck, on its way to the
cock-pit. As the scamp of a servant boy who carried the dish came
abreast of the gangway, I saw him cock his eye aloft as if to see how
I relished the prospect. No hawk, or eagle, or vulture, ever gazed
from the sky more wistfully upon its prey beneath, than I did upon the
banquet I was doomed never to taste. What was still more
provoking, each of my messmates, as he ran down the quarter-deck
ladder, on being summoned to dinner, looked up at me and grinned;
and one malicious dog patted his fat paunch—as much as to say,
‘What a glorious feast we are to have! Should not you like a bit?’
CHAPTER IX.
KEEPING WATCH.
With a few exceptions, every person on board a man-of-war keeps

watch in his turn: and as this is one of the most important of the
wheels which go to make up the curious clock-work of a ship’s
discipline, it seems to deserve a word or two in passing.
The officers and midshipmen are generally divided into three
watches—First, Second, and Third. As the senior lieutenant does not
keep watch, the officer next in rank takes the First, the junior
lieutenant the Second, and the master the Third watch, in ships
where there are not more than three lieutenants. Under each of
these chiefs there is placed a squad of midshipmen; the principal
one of whom is mate of the watch, the next in seniority is stationed
on the forecastle, and after him comes the poop mid. The youngsters
remain on the lee-side of the quarter-deck, along with the mate of
the watch. For it must be observed, that no one but the captain, the
lieutenants, the master, surgeon, purser, and marine officer, is ever
allowed, upon any occasion whatsoever, to walk on the weather
side. This custom has become so much a matter of course, that I
hardly remember asking myself before, what may have been the
origin of the regulation? The chief purpose, no doubt, is to draw a
strong line of distinction between the different ranks; although,
independently of this, the weather side is certainly the most
convenient to walk upon when the ship is pressed with sail: it is also
the best sheltered from wind and rain; and the view both low and
aloft is more commanding than it is from to leeward.
Every person, also, not excepting the captain, when he comes on
the quarter-deck, touches his hat; and as this salutation is supposed
to be paid to this privileged spot itself, all those who at the moment
have the honour to be upon it are bound to acknowledge the
compliment. Thus, even when a midshipman comes up, and takes
off his hat, all the officers who are walking the deck, the Admiral
included, if he happens to be of the number, touch their hats
likewise.
So completely does this form grow into a habit, that in the darkest
night, and when there may not be a single person near the
hatchway, it is invariably attended to, with the same precision.
Indeed, when an officer of the Navy happens to be on board a
merchant ship, or a packet, he finds it difficult to avoid carrying his
hand to his hat every time he comes on deck. I, for one, at least, can
never get over the feeling, that it is rude to neglect this ceremony,
and have often, when on board passage vessels, wondered to see
gentlemen so deficient in good breeding, as to come gaping up the
hatchway, as if their hats were nailed to their heads, and their hands
sewed into their breeches-pockets!
Of course, each person in the watch has a specific duty to attend
to, as I shall endeavour to describe presently; but, first, it may be
well to mention the ingenious arrangement of the hours by which the
periods of watching are equally distributed to all.
In speaking of the three watches, it will perhaps avoid confusion,
and rather simplify the description, to call them, for a moment, not
First, Second, and Third, as they are named on board ship, but to
designate them by the letters A, B, and C.
Let us begin, then, by supposing that A’s watch commences at 8
o’clock in the evening; the officer and his party remain on deck till
midnight, four hours being one period. This is called the First watch.
B is next roused up, and keeps the Middle watch, which lasts from
midnight till 4 o’clock. C now comes up, and stays on deck till 8,
which is the Morning watch. A then returns to the deck, where he
walks till noon, when he is relieved by B, who stays up till 4. If C
were now to keep the watch from 4 to 8, of course A would again
have to keep the First watch on the second night, as he did at first
starting; and all the others, in like manner, would have to keep, over
again, exactly the same watches, every night and day. In order to
break this uniform recurrence of intervals, an ingenious device has
been hit upon to produce a constant and equitable rotation. When or
where this plan was invented, I do not know, but I believe it exists in
the ships of all nations.
The period from 4 o’clock in the afternoon till 8 in the evening,
instead of constituting one watch, is divided into two watches, of a
couple of hours each. These, I don’t know why, are called the Dog
watches. The first, which lasts from 4 to 6 o’clock, belongs, on the
second day, according to the order described above, to C, who is, of
course, relieved at 6 o’clock by A. This alteration, it will be observed,
gives the First watch (from 8 to midnight) to B, on the second night;
the Middle (from midnight to 4) to C; and the Morning watch (from 4
to 8) to A; the Forenoon watch (from 8 to noon) to B; and the
Afternoon (from noon to 4) to C. The first Dog watch (from 4 to 6) will
now be kept by A, the second Dog watch (from 6 to 8) by B, and so
on, round and round. By this mechanism, it will easily be perceived,
the officers, on each succeeding day, have a watch to keep, always
one stage earlier than that which they kept on the day before. Thus,
if A have the Morning watch one night, he will have the Middle watch
on the night following, and the First watch on the night after that
again. The distribution of time which this produces is very unequal,
when the short period of twenty-four hours only is considered; but
the arrangement rights itself in the course of a few days. On the first
day, A has ten hours’ watch to keep out of the twenty-four, B eight,
and C only six. But on the next day, A has only six hours, while B
has ten, and C eight; while, on the third day, A has eight, B six, and
C ten hours’ watching; and so on, round and round, from year’s end
to year’s end.
This variety, to a person in health and spirits, is often quite
delightful. Each watch has its peculiar advantages; and I need hardly
add, that each likewise furnishes an ample store of materials for
complaining, to those discontented spirits whose chief delight is to
coddle up grievances, as if, forsooth, the principal object of life was
to keep ourselves unhappy, and to help to make others so!
The First watch (8 o’clock to midnight) which comes after the
labour of the day is done, and when every thing is hushed and still,
carries with it this great recommendation, that, although the hour of
going to bed is deferred, the night’s rest is not afterwards broken in
upon. The prospect of ‘turning in’ at midnight, and being allowed to
sleep till seven in the morning, helps greatly to keep us alive and
merry during the First watch, and prevents the excitement of the past
day from ebbing too fast. On the other hand, your thorough-bred
growlers are apt to say, it is a grievous task to keep the First watch,
after having gone through all the toil of the day, and, in particular,
after having kept the Afternoon watch (noon to 4 o’clock,) which, in
hot climates, is always a severe trial upon the strength. Generally
speaking, however, I think the First watch is the least unpopular; for,
I suppose, no mortal, whatever he might think, was ever found so
Quixotic as to profess openly that he really liked keeping watch.
Such a paradox would be famously ridiculed on board ship!
The Middle watch is almost universally held to be a great bore;
and certainly it is a plague of the first order, to be shaken out of a
warm bed at midnight, when three hours of sound sleep have sealed
up our eyelids all the faster, and steeped our senses in forgetfulness,
and in repose, generally much needed. It is a bitter break, too, to
have four good hours sliced out of the very middle of the night’s rest,
especially when this tiresome interval is to be passed in the cold and
rain, or, which is often still more trying, in the sultry calm of a smooth,
tropical sea, when the sleepy sails, as wet with dew as if they had
been dipped overboard, flap idly against the masts and rigging, but
so very gently as barely to make the reef points patter-patter along
the canvass, with notes so monotonous, that the bare recollection of
their sound almost sets me to sleep, now.
Nevertheless, the much-abused Middle watch has its advantages,
at least for those ardent young spirits who choose to seek them out,
and whose habit it is to make the most of things. There are full three
hours and a half of sound snooze before it begins, and as long a
‘spell of sleep’ after it is over. Besides which, the mind, being rested
as well as the body, before the Middle watch begins, both come to
their task so freshly, that, if there be any hard or anxious duties to
execute, they are promptly and well attended to. Even if there be
nothing to do but pace the deck, the thoughts of an officer of any
enthusiasm may contrive to find occupation either in looking back, or
in looking forward, with that kind of cheerfulness which belongs to
youth and health usefully employed. At that season of the night every
one else is asleep, save the quarter-master at the conn, the
helmsman at the wheel, and the look-out men at their different
stations, on the gangways, the bows, and the quarters. And except,
of course, the different drowsy middies, who, poor fellows! keep
tramping along the quarter-deck backwards and forwards, counting
the half-hour bells with anxious weariness; or looking wistfully at the
sand-glass, which the sentry at the cabin-door shakes ever and
anon, as if the lazy march of time, like that of a tired donkey, could
be accelerated by jogging.
But the joyous Morning watch is very naturally the universal
favourite. It is the beginning of a new day of activity and enterprise.
The duties are attacked, too, after a good night’s rest; so that, when
the first touches of the dawn appear, and the horizon, previously lost
in the black sky, begins to shew itself in the east, there comes over
the spirits a feeling of elasticity and strength, of which even the
dullest are not altogether insensible. In war time, this is a moment
when hundreds of eyes are engaged in peering all round into the
twilight; and happy is the sharp-sighted person who first calls out,
with a voice of exultation—
“A sail, sir—a sail!”
“Whereabouts?” is the eager reply.
“Three or four points on the lee-bow, sir.”
“Up with the helm!” cries the officer. “Set the top-gallant and royal
studding-sails—rig out the fore-top-mast studding-sail boom!
Youngster, run down and tell the captain there is a stranger on the
lee-bow—and say that we are making all sail. She looks very
roguish.”
As the merry morning comes dancing gloriously on, and other
vessels hove in sight, fresh measures must be taken, as to the
course steered, or the quantity of sail to be set. So that this period of
the day, at sea, in a cruising ship, gives occasion, more perhaps
than any other time, for the exercise of those stirring qualities of
prompt decision, and vigour in the execution of every purpose,
which, probably, form the most essential characteristics of the
profession.
The Morning watch, also, independent of the active employment it
hardly ever fails to afford, leaves the whole day free, from eight
o’clock till four in the afternoon. Many a previously broken resolution
is put off to this period, only to be again stranded. To those, however,
who choose to study, the certainty of having one clear day in every
three, free from the distraction of all technical duties, is of the
greatest consequence; though, it must be owned that, at the very
best, a ship is but a wretched place for reading. The eternal motion,
and the infernal, noise, almost baffle the most resolute students.
For a hungry midshipman (when are they not hungry!) the Morning
watch has attractions of a still more tender nature. The mate, or
senior man amongst them, is always invited to breakfast with the
officers at eight o’clock; and one or two of the youngsters, in turn,
breakfast with the captain at half-past eight, along with the officer of
the morning watch and the first lieutenant, who, in many ships, is the
constant guest of the captain, both at this meal and at dinner.
The officer of the Forenoon watch, or that from eight to noon,
invariably dines with the captain at three o’clock; and as the ward-
room dinner is at two, exactly one hour before that of the captain, the
officer who has kept the Forenoon watch again comes on deck, the
instant the drum beats “The Roast Beef of Old England,” the well
known and invariable signal that the dinner of the officers is on the
table. His purpose in coming up is to relieve, or take the place of his
brother officer who is keeping the Afternoon watch, till three o’clock
arrives, at which hour the captain’s dinner is ready. The same
interchange of good offices, in the way of relief, as it is called, takes
place amongst the midshipmen of the Forenoon and Afternoon
watches. It is material to observe, however, that all these
arrangements, though they have the graceful air of being pieces of
mutual and voluntary civility, have become quite as much integral
parts of the ordinary course of nautical affairs as any other
established ordinance of the ship.
On Sunday, the captain always dines with the officers in the ward-
room; and although ‘shore-going people’ sometimes take upon
themselves to quiz these periodical, and, Heaven knows! often
formal, dinner parties, there can be no doubt that they do contribute,
and that in a most essential degree, to the maintenance of strict
discipline on board ship. Indeed, I believe it is now generally
admitted, that it would be next to impossible to preserve good order
in a man-of-war, for any length of time, without this weekly
ceremonial, coupled, of course, with that of the officers’ dining, in
turn, with their captain.
We know that too much familiarity breeds contempt; but, in
situations where there is of necessity much intercourse, too little
familiarity will as inevitably breed ill-will, distrust, apprehension, and
mutual jealousy. The difficulty lies in regulating with due caution this
delicate sort of intimacy, and in hitting the exact mean between too
much freedom and too much reserve of manner. The proverb points
out the evil clearly enough, but leaves us to find the remedy. In the
Navy, long experience seems to have shewn, that this important
purpose can be best accomplished by the captain and his officers
occasionally meeting one another at table—not capriciously, at
irregular intervals, or by fits and starts of favour, as the humour suits,
but in as fixed an order, as if the whole of this social intercourse were
determined by Admiralty regulation.
It will readily be understood by any one who has attended much to
the subject of discipline, and will be felt, I should think, more or less,
by all persons who have been engaged personally in the
management of a house, a regiment, a ship, a shop, or any other
establishment in which distinctions of rank and subdivisions of labour
prevail, that nothing ever does, or can go on well, unless, over and
above the mere legal authority possessed by the head, he shall carry
with him a certain amount of the good-will and confidence of those
under him. For it is very material, in order to balance, as it were, the
technical power with which the chief of such establishment is armed,
that there should be some heartiness—some real cheerfulness,
between him and those he commands. Accordingly, the obedience
which they yield to him should not be entirely the result either of

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Neuroblastoma: Clinical and Surgical

Management Sabine Sarnacki

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ISBN 978-3-030-18395-0 ISBN 978-3-030-18396-7 (eBook)

© Springer Nature Switzerland AG 2020

Part I Epidemiology, Biology and Pathology Assessment

Part III Clinical Management

11 Low- and Intermediate-Risk Neuroblastoma������������������������������������������ 205

1.1 Descriptive Epidemiology

In the International classification of disease for oncology (ICD-O-3) [1], neuroblas-

J. Clavel (*) · B. Lacour

© Springer Nature Switzerland AG 2020 3

In this chapter, the epidemiological features of neuroblastomas are described

1.1.1 Incidence and Epidemiological Features

1.2.1 Perinatal Characteristics

Table 1.3 (continued)

Regarding gestational age, no pattern of a positive or inverse association has

1.2.2 Maternal Vitamin or Folic Acid Intake Around Pregnancy

Breastfeeding was reported to reduce risk of neuroblastoma in the COG North-­

1.2.4 Congenital Malformations

1.2.5 Parental Smoking and Alcohol Consumption

Overall, literature suggests that maternal tobacco smoking is associated with a

1.2.6 Pesticides Exposures

Exposures to pesticides have been the most investigated environmental exposures,

reported increased risk of neuroblastoma with farming or pesticides use. Two

1.2.7 Other Factors

Associations with maternal medication use, perinatal infections, parental occupa-

2.2 Hereditary Genetic Factors

Several observations corroborate the hypothesis of a role of underlying hereditary

© Springer Nature Switzerland AG 2020 17

polyalanine sequence of PHOX2B are mainly observed in patients with a curse of

2.2.1 Somatic Genetic Alterations

2.2.1.1 Copy-Number Alterations

comparative genomic hybridization (CGH) or single nucleotide polymorphism

2.2.1.2 Single-Gene Mutations

alternate lengthening of telomeres (ALT), which may be associated with primary

2.2.1.3 Expression Profiles

2.2.1.4 Spatial and Temporal Heterogeneity

With a few exceptions, every person on board a man-of-war keeps

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Part I Epidemiology, Biology and Pathology Assessment

Part III Clinical Management

11 Low- and Intermediate-Risk Neuroblastoma�� 205

1.1 Descriptive Epidemiology

1.1.1 Incidence and Epidemiological Features

1.2.1 Perinatal Characteristics

1.2.2 Maternal Vitamin or Folic Acid Intake Around Pregnancy

Breastfeeding was reported to reduce risk of neuroblastoma in the COG North-

1.2.4 Congenital Malformations

1.2.5 Parental Smoking and Alcohol Consumption

1.2.6 Pesticides Exposures

1.2.7 Other Factors

2.2 Hereditary Genetic Factors

2.2.1 Somatic Genetic Alterations

2.2.1.1 Copy-Number Alterations

2.2.1.2 Single-Gene Mutations

2.2.1.3 Expression Profiles

2.2.1.4 Spatial and Temporal Heterogeneity