1063
C HA PTER   89
Childhood Leukaemias and Lymphomas
Keith Morley & Jennifer Huang
Dermatology Program, Boston Children’s Hospital, Boston, MA, USA
Leukaemia, 1063 Hodgkin disease, 1067
Abstract
Childhood leukaemias and lymphomas are among the most com-
mon of paediatric malignancies. Cutaneous involvement is a common
occurrence and often carries significant prognostic implications.
Leukaemia
Key points
• Congenital and childhood leukaemias have provided many
insights into the genetic events responsible for oncogenesis.
• In general, the development of leukaemia cutis indicates a
poorer prognosis.
• The frequency of leukaemia cutis seems to be higher among
children than adults.
• Following treatment, these patients may face many long‐term
cutaneous sequelae.
Introduction. Leukaemias are the most common child-
hood cancer, accounting for approximately one third of
all malignancies in this age group [1]. Dermatologists and
paediatricians must work together to quickly recognize
cutaneous signs of leukaemia as the skin can often pro-
vide early clues to this disease. In this chapter, we will
touch upon the multiple dermatological manifestations of
leukemia that have been identified, including:
• leukaemic infiltration of the skin and subcutaneous tis-
sue (leukaemia cutis)
• cutaneous lesions associated with bone marrow dys-
function (petechiae, purpura, ecchymoses or cutaneous
erythropoiesis in infants manifesting as blueberry muf-
fin lesions)
• toxic or immunological responses to tumour antigens
(‘leukaemids’)
• paraneoplastic conditions such as ichthyosis,
hyperpigmentation, hyperkeratosis of the palms and
soles, severe eczematous eruptions, Sweet syndrome,
Harper’s Textbook of Pediatric Dermatology, Fourth Edition. Edited by Peter Hoeger, Veronica Kinsler and Albert Yan.
© 2020 John Wiley & Sons Ltd. Published 2020 by John Wiley & Sons Ltd.
As many of these lesions are morphologically nonspecific, clinico-
pathological correlation is often required in these cases. Prompt
recognition and early multidisciplinary treatment are crucial for
optimal outcomes.
pyoderma gangrenosum, erythema multiforme, vascu-
litis and opportunistic infections
• cutaneous manifestations resulting from chemotherapy,
radiation or photosensitizing drugs.
Epidemiology and pathogenesis. Acute lymphoblastic
leukaemia (ALL) comprises 75–80% of all leukaemias
diagnosed in children [1,2]. The incidence is estimated
to be 3.4 cases per 100 000 children younger than age
15, with the peak incidence between ages 2  and
5 years [1]. Acute myeloid leukaemia (AML) accounts
for most of the remaining 20%, with a much smaller
number representing rare cases of the remaining leu-
SECTION 18: LYMPHOCYTIC
kaemias including chronic myeloid forms, acute gran-
ulocytic leukaemia and plasmacytoid dendritic cell
leukaemias [3–5]. While rare  and more often seen
in  elderly patients, blastic plasmacytoid dendritic
DISORDERS
cell  neoplasm is worth mentioning as  approximately
85% of cases demonstrate cutaneous involvement at
presentation [6].
Classifying childhood leukaemia further, it is defined
as congenital when diagnosed at birth, neonatal during
the first month of life, and as leukaemia of infancy after
1 month of life. Congenital leukaemia amounts to less
than 1% of childhood leukaemia cases but is associated
with the presence of leukaemia cutis in up to 30% of
cases [7–11]. While leukaemia cutis is associated with
very poor prognosis in adult leukaemia, the natural his-
tory of ­congenital leukaemia is not altered by leukaemia
cutis [9].
Congenital and childhood leukaemias have provided
many insights into the genetic events responsible for
oncogenesis, particularly in the context of inherited
 1064 Section 18  Lymphocytic Disorders

c­onditions known to predispose to leukaemia. These

include diseases with defects in DNA damage repair
(Fanconi anaemia, ataxia‐telangiectasia, Bloom syndrome),
cell cycle and differentiation defects (RASopathies, such as
neurofibromatosis type 1 and Noonan syndrome) and ane-
uploidy‐associated conditions (exemplified by trisomy 21)
[12]. Children with trisomy 21 carry a 10–20‐fold higher
risk of developing acute leukaemia compared to the gen-
eral population and are at particularly high risk for acute
megakaryoblastic leukaemia (500 times more likely than
the general population) [12]. In young trisomy 21 patients,
leukaemia must be distinguished from a transient vesicu-
lopustular myeloproliferative disorder which occurs in
approximately 5–10% of this population and which usually
resolves spontaneously within several months [12].

Clinical features and differential diagnosis. The first Fig. 89.1  Small purple papules diagnosed on biopsy as leukaemia cutis
s ystemic manifestations of leukaemia typically
­ from underlying acute lymphoblastic leukaemia (ALL).
include ­ anorexia, irritability and lethargy. Other
­s ystemic symptoms follow, including fever, pallor due
to anaemia, ­lymphadenopathy, hepatosplenomegaly,
bleeding, bone pain and arthralgia associated with
periosteal or bony involvement. The frequency of leu-
kaemia cutis seems to be higher among children than
adults, with cutaneous lesions the initial manifesta-
tion in up to 50% of infants [9–11]. Leukaemia cutis is
more commonly associated with AML than ALL, with
skin involvement seen in up to 50% of patients with
acute myelomonocytic (AMMoL) and monocytic
(AMoL) leukaemia [8].
Most cases of leukaemia cutis occur after a diagnosis of
systemic leukaemia has been established. Concomitant
involvement of skin and systemic leukaemia has been
observed in up to one third of cases. Occasionally (less Fig. 89.2  Multiple purpuric papules scattered over the head in a case of
SECTION 18: LYMPHOCYTIC

10% of cases), skin infiltration can occur before bone leukemia cutis from acute lymphoblastic leukaemia (ALL).
marrow or peripheral blood involvement and in the
­
absence of systemic symptoms [13]. The term ‘aleukaemic
DISORDERS

leukaemia cutis’ or ‘primary extramedullary leukaemia’

has been used for this uncommon event, which occurs
predominantly in patients with AML and by definition
requires the presence of skin involvement for longer than
one month without involvement of the blood or bone mar-
row [3]. There are no consistent predictable demographic
or clinical differences that distinguish patients who have
leukaemia with or without leukaemia cutis. As many as
90% of patients with leukaemia cutis also have involve-
ment of other extramedullary sites, with occurrence in the
meninges particularly frequent (40% of cases) [10].
Patients with leukaemia cutis may have single or mul-
tiple skin lesions. The lesions may be described as viola-
ceous, red‐brown or haemorrhagic macules, papules,
nodules and/or plaques of varying sizes (Figs 89.1, 89.2,
89.3 and 89.4). Erythematous papules and nodules are Fig. 89.3  Small purpuric nodule in patient with acute lymphoblastic
reported as the most common clinical presentation. Skin leukaemia (ALL): Candida albicans infection.
lesions may be firm but not stony hard. Tumours of mono-
cytic leukaemia tend to be large and purplish or ‘plum‐ [10,13]. Green tumours or granulocytic sarcomas (for-
coloured’ (Fig.  89.5). In chronic juvenile myelocytic merly called chloromas), lesions pathognomonic for
leukaemia, small prurigo‐like red papules are characteris- ­leukaemia, can arise at the same time as acute granulo-
tic (Fig.  89.6) [10,14,15]. Aleukaemic leukaemia cutis cytic leukaemia or may precede the disease by one or
lesions are usually widespread and papulonodular more years before the underlying disorder becomes
 Chapter 89  Childhood Leukaemias and Lymphomas 1065

Fig. 89.7  Granulocytic sarcoma (chloroma) of the retroorbital tissue in an

18‐month‐old girl with acute monoblastic leukaemia (AML).
Fig. 89.4  Acute monoblastic leukaemia (AML) M5 type in a newborn infant.

apparent (Fig. 89.7). Seen primarily in children, granulo-

cytic sarcomas, which result from infiltration of immature
granulocytic cells, may also arise at sites other than the
skin, such as the bones, lacrimal glands, retroorbital
­tissues, lymph nodes and breast. Lesions vary from 1 to
3 cm in diameter and the green colour is caused by the
enzyme myeloperoxidase.
The legs are involved most commonly by leukaemia
cutis, followed by the arms, back, chest, scalp and face.
A particular type of leukaemia can produce different
skin lesions during the course of the disease, even in the
same patient [15]. Leukaemic infiltrates may arise in
scars from recent surgery, burns, trauma, sites of intra-
muscular or intrathecal injections and lesions of herpes
simplex or herpes zoster infections. Moreover, specific
cutaneous infiltrates have presented at the sites of prior

SECTION 18: LYMPHOCYTIC

chickenpox virus eruptions and Borrelia burgdoferi infec-
tions [16].
In addition, leukaemic plaques can cause thickening of
the scalp, eyebrows and cheeks, producing leonine facies.

Fig. 89.5  Purplish tumours of acute monoblastic leukaemia (AML) arise in
a puncture site of a patient treated previously for acute lymphoblastic
leukaemia (ALL).
Fig. 89.6  Small red prurigo‐like papules in leukaemia cutis with underlying
juvenile chronic myelocytic leukaemia.
DISORDERS
Rarely encountered clinical manifestations include eryth-
roderma, chronic paronychia, palmar plaques, bullous
eruptions, scrotal ulcers and subungual lesions [10,16].
Especially common in AMoL and AMMoL, patients with
oral involvement may present with painful teeth, gingival
hyperplasia, friable bleeding gums or ulcerations of the
buccal or gingival mucosa.
Leukaemids are skin findings that arise in the context
of leukaemia which are not related to infiltration of leu-
kaemic cells themselves. These reactions are presumed to
result from toxic effects of the underlying disorder and
have a variety of manifestations including prurigo‐like
papules, maculopapular eruptions, vesicobullous lesions,
urticaria, generalized erythroderma, exfoliative hyper-
pigmentation, erythema multiforme, Sweet syndrome
and erythema nodosum [10].
Regarding differential diagnoses, several cutaneous
disorders can present as similar nodules or plaques
and histopathology is often required to distinguish
amongst them. In neonates, congenital infections
(TORCH infections), haemolytic diseases secondary to
Rh incompatibility, neuroblastoma, Langerhans cell
 1066 Section 18  Lymphocytic Disorders
histiocytosis, among others, can all lead to cutaneous
erythropoiesis similar to congenital leukaemia
(Fig. 89.8). Also, transient myeloproliferative disorder
in neonates with trisomy 21 must be distinguished
from true leukaemia. Opportunistic infections such as
atypical mycobacterial and deep or invasive fungal
infections are important to exclude as certain genetic
conditions such as GATA2 deficiency may predispose
to both neoplasia and infections [17].
Laboratory/histology findings. The diagnosis of leukae-
mia cutis is based on the morphological pattern of skin
infiltration, cytological features and, most importantly,
immunophenotyping of the tumour cells. Correlation
with clinical data and bone marrow and peripheral blood
findings is often helpful to confirm the diagnosis.
Histological examination of leukaemia cutis will reveal a
dermal infiltrate with a variable appearance depending
on the specific leukaemic cell type (Fig. 89.9). These infil-
trates often show a perivascular and/or periadnexal pat-
tern of involvement or a dense diffuse/interstitial or
nodular infiltrate involving the dermis and subcutis with
sparing of the upper papillary dermis (Grenz zone).
SECTION 18: LYMPHOCYTIC
DISORDERS
Fig. 89.8  Congenital monocytic leukaemia presenting as blueberry muffin
syndrome.
Fig. 89.9  Histological image of the patient in Fig. 89.5, showing dense
infiltrate of blast cells deeply situated in the dermis (haematoxylin and
eosin, ×150).
A  variety of chromosomal abnormalities have been
reported in patients with childhood leukaemia beyond
the scope of this chapter [10,12].
Treatment and prevention. In general, the development
of leukaemia cutis indicates a poorer prognosis [8].
Patients with congenital leukaemia seem to be an excep-
tion because leukaemia cutis does not necessarily confer a
worse prognosis. Leukaemia cutis is a local manifestation
of an underlying systemic disease; therefore, the treat-
ment should be aimed at eradicating the disease via
­systemic therapies. Following treatment, these patients
may face long‐term cutaneous sequelae ranging from
benign but potentially disfiguring (increased density of
basal naevi, alopecia, scars) to malignant (increased risk
of melanoma and nonmelanoma skin cancer). Based on
these risk factors, the Children’s Oncology Group has
proposed regular, long‐term dermatological follow‐up
for survivors [18].
References
1 Anderson PC, Stotland MA, Dinulos JG, Perry AE. Acute lymphocytic
leukemia presenting as an isolated scalp nodule in an infant. Ann
Plast Surg 2010;64(2):251–3.
2 Parker BR. Leukemia and lymphoma in childhood. Radiol Clin North
Am 1997;35:1495–516.
3 Burnett MM, Huang MS, Seliem RM. Case records of the
Massachusetts General Hospital. Case 39‐2007. A 5‐month‐old girl
with skin lesions. N Engl J Med 2007;357(25):2616–23.
4 Hama A, Kudo K, Itzel BV et al. Plasmacytoid dendritic cell leukemia
in children. J Pediatr Hematol Oncol 2009;31(5):339–43.
5 Nguyen CM, Stuart L, Skupsky H et al. Blastic Plasmacytoid dendritic
cell neoplasm in the pediatric population: a case series and review of
the literature. Am J Dermatopathol 2015;37(12):924–8.
6 Jegalian AG, Buxbaum NP, Facchetti F et al. Blastic plasmacytoid den-
dritic cell neoplasm in children: diagnostic features and clinical impli-
cations. Haematologica 2010;95(11):1873–9.
7 Lee EG, Kim TH, Yoon MS, Lee HJ. Congenital leukemia cutis preced-
ing acute myeloid leukemia with t(9;11)(p22;q23), MLL‐MLLT3.
J Dermatol 2013;40(7):570–1.
8 Zhang IH, Zane LT, Braun BS et al. Congenital leukemia cutis with
subsequent development of leukemia. J Am Acad Dermatol 2006;
54:22–7.
9 Resnik KS, Brod BB. Leukemia cutis in congenital leukemia: analysis
and review of the world literature with report of an additional case.
Arch Dermatol 1993;129:1301–6.
10 Cho‐Vega JH, Medeiros LJ, Prieto VG, Vega F. Leukemia cutis. Am J
Clin Pathol 2008;129:130–42.
11 Zhang IH, Zane LT, Braun BS et  al. Congenital leukemia cutis with
subsequent development of leukemia. J Am Acad Dermatol 2006;
54(2 Suppl):22–7.
12 Seif AE. Pediatric leukemia predisposition syndromes: clues to
understanding leukemogenesis. Cancer Genet 2011;204(5):227–44.
13 Hejmadi RK, Thompson D, Shah F, Naresh KN. Cutaneous presenta-
tion of aleukemic monoblastic leukemia cutis: a case report and
review of literature with focus on immunohistochemistry. J Cutan
Pathol 2008;35(Suppl 1):46–9.
14 Angulo J, Haro R, González‐Guerra E et al. Leukemia cutis presenting
as localized cutaneous hyperpigmentation. J Cutan Pathol 2008;
35:662–5.
15 Watson KM, Mufti G, Salisbury JR et al. Spectrum of clinical presenta-
tion, treatment and prognosis in a series of eight patients with leuke-
mia cutis. Clin Exp Dermatol 2006;31:218–21.
16 Robax E, Robax T. Skin lesions in chronic lymphocytic leukemia.
Leuk Lymphoma 2007;48:855–65.
17 Hyde RK, Liu PP. GATA2 mutations lead to MDS and AML. Nat
Genet 2011;43(10):926–7.
18 www.survivorshipguidelines.org/pdf/2018/COG_LTFU_
Guidelines_v5.pdf
 Chapter 89  Childhood Leukaemias and Lymphomas
Hodgkin disease
Key points
• Cutaneous manifestations are found in 13–40% of patients
with Hodgkin disease.
• Primary cutaneous Hodgkin disease, or skin involvement
without disease at any other site, is exceptionally rare.
• The most well‐recognized paraneoplastic finding is severe
pruritus.
• The prognosis of Hodgkin lymphoma has improved substantially
over recent decades.
Introduction. Lymphoma is the third most common can-
cer in children following brain/central nervous system
malignancies. It constitutes a group of malignant neopla-
sias derived from B or T lymphocytes and has been subdi-
vided into two broad categories: Hodgkin disease
(alternatively known as Hodgkin lymphoma) and non‐
Hodgkin lymphomas (see Chapter 88). Hodgkin disease
is a malignant lymphoma in which the Reed–Sternberg
giant cell (a large, typically multinucleated cell with
abundant cytoplasm) is the central histological feature.
Epidemiology and pathogenesis. Hodgkin disease causes
approximately 4% of childhood malignancies and occurs
primarily in two age groups. The first peak occurs in
­teenagers and young adults in the middle to late 20s; a
second peak occurs in adults over the age of 50 years [1].
Hodgkin disease rarely occurs before the age of 5 years.
The Hodgkin and Reed–Sternberg (HRS) cells represent
clonal tumour populations derived from germinal centre
B cells [2]. Although its aetiology remains unknown,
Epstein–Barr virus (EBV) infection is associated with a
proportion of cases: EBV genomes are present in HRS
cells, and viral proteins, including latent membrane pro-
tein 1 (LMP1) which has oncogenic potential, are
expressed [3–5]. Disease occurring in early childhood and
older adult age groups is more likely to be EBV associated
than for young adult cases [6,7]. It has been estimated that
4.5% of Hodgkin disease cases are familial [3–5,8].
A higher frequency of the disease has been noted in
males, white people and patients with underlying immu-
nodeficiency. The gene expression profile is that of an
aberrant germinal centre B lymphocyte that resists apop-
tosis through CD40 signalling and NF‐κB activation [9].
NF‐κB triggers cell proliferation and provides a molecular
basis for these cells’ aberrant growth and cytokine gene
expression. In EBV‐associated Hodgkin disease, the
­activation of NF‐κB is induced by viral LMP1 [10,11].
Clinical features and  differential diagnosis. In 90% of
cases, Hodgkin disease is initially limited to the lymph
nodes. It presents as a painless enlargement of the cervical
lymph nodes, and occasionally of the supraclavicular, axil-
lary or inguinal lymph nodes. Usually, the enlargement
is  firm, nontender and often discrete, involving single
or  multiple lymph nodes. The patient’s condition may
1067
­ therwise initially be normal but with progressive involve-
o
ment, fever, anaemia and weight loss are common.
Cutaneous manifestations are found in 13–40% of
patients. As in leukaemia, these manifestations are often
nonspecific. Lymphoma cutis (analogous to leukaemia
cutis) is cutaneous involvement that typically occurs in
areas of skin distal to lymph nodes containing a tumour.
It can be secondary to retrograde lymphatic spread from
tumour‐involved lymph nodes, direct extension into skin
by tumour cells in underlying lymph nodes or haematog-
enous spread of the tumour. It generally presents as pink,
reddish‐brown, violaceous, plum‐coloured or dark pur-
ple papules or nodules which often coalesce to form large
plaques or tumours (Figs 89.10 and 89.11). Varying from a
few millimetres to several centimetres in diameter, lesions
are usually localized to the upper trunk, neck and scalp,
and ulcerations frequently occur (Fig. 89.12). Cutaneous
lesions generally occur as a manifestation of late‐stage
disseminated disease and often herald a poor prognosis
[12]. Primary cutaneous Hodgkin disease, or skin involve-
ment without disease at any other site, is far less common,
with only sporadic, predominantly adult cases reported
[12–15]. To qualify as primary cutaneous Hodgkin dis-
ease, lymphoma in the skin must be demonstrated
without any nodal involvement and no evidence of
­
extracutaneous dissemination even three months after
­
diagnosis.
The most well‐recognized paraneoplastic finding is
severe pruritus. Other nonspecific findings such as urti-
caria, purpura, papules, pyoderma, hyperpigmentation,
hyperpigmented scars, exfoliative erythroderma, acquired
ichthyosis, atopic dermatitis, nonspecific ­eczematous or
psoriasiform plaques, prurigo nodularis, h ­ yperkeratosis
SECTION 18: LYMPHOCYTIC
DISORDERS
Fig. 89.10  Pink papules over the shoulder of a 13‐year‐old boy with
Hodgkin disease.
 1068 Section 18  Lymphocytic Disorders
Fig. 89.11  Hodgkin disease: red nodule on the heel.
Fig. 89.12  Ulcerated lesions in the infraclavicular region of a 16‐year‐old
girl with Hodgkin disease.
SECTION 18: LYMPHOCYTIC
of the palms and soles, loss of body hair, nail dystrophy,
erythema nodosum, granulomas, erythema multiforme
and herpes simplex and herpes zoster virus infection have
also been described in association with Hodgkin disease
DISORDERS
[8,12]. Vesicular and bullous lesions, although rare, usu-
ally appear as a terminal manifestation. A case of angioker-
atoma corporis diffusum developing in a patient with
Hodgkin disease was presented as a possible new para-
neoplastic phenomenon [16].
The differential diagnoses for Hodgkin disease include
other lymphoproliferative disorders (lymphomatoid papulo-
sis, anaplastic large cell lymphoma, granulomatous slack
skin disease, leukaemia), soft tissue malignancies (dermatofi-
broma sarcoma protuberans, Kaposi sarcoma, leiomyomas)
and infections (tuberculosis, atypical m­ ycobacterial, fungal).
Histological differentiation is often essential.
Laboratory/histology findings. Classic Hodgkin disease
is a monoclonal lymphoid neoplasm composed of mono-
nuclear Hodgkin cells and multinucleated HRS residing
in an infiltrate containing a variable mixture of nonneo-
plastic small lymphocytes, eosinophils, neutrophils, his-
tiocytes, plasma cells, fibroblasts and collagen fibres.
Based on the characteristics of the reactive infiltrate and
the morphology of HRS cells, four histological subtypes
have been distinguished.
• Nodular sclerosing variant, which is the most common
form in children and adolescents.
• Mixed cellularity variant, which is the second most com-
mon form.
• Lymphocytic predominant variant, in which there are few
Reed–Sternberg cells, and the prognosis is usually
good.
• Lymphocytic depletion variant, which is the least common
and has the least favourable prognosis, with patients
presenting with widespread disease [3].
HRS cells are positive for CD30 in nearly all cases, posi-
tive for CD15 in the majority of cases, usually CD45 nega-
tive, and consistently negative for J chain, CD75 and
macrophage‐specific markers such as the PG‐M1 epitope
of the CD68 molecule [1–3].
Treatment and  prevention. The prognosis of Hodgkin
lymphoma has improved substantially over recent dec-
ades. In early (stage I) disease where only a single lymph
node or extranodal site is involved, over 90% of patients
can be cured by radiation therapy alone or in combination
with multiagent chemotherapy such as vincristine, pro-
carbazine, prednisone, doxorubicin, bleomycin or dacar-
bazine [17–19]. Primary cutaneous Hodgkin disease is
thought to have a better overall prognosis than nodal dis-
ease, responding well to radiotherapy and/or surgicial
excision. In advanced nodal disease, a combined approach
(radiation therapy, total nodal irradiation and various
combinations of chemotherapeutic agents) is usually
required. As a consequence of successful therapy for
initial malignancies, the risk of second malignant
­
­neoplasms has increased and mandates regular multidis-
ciplinary follow‐up [20,21].
Acknowledgement
The authors gratefully acknowledge the authors of the
previous chapter, Drs Adrián‐Martín Pierini, Andrea
Bettina Cervini and Marcela Bocian, who have kindly
given permission for us to reuse selected images and
material.
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 Chapter 89  Childhood Leukaemias and Lymphomas
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SECTION 18: LYMPHOCYTIC
DISORDERS