L C H O F T H E M A X I L L A E .
T R E AT M E N T A N D O RT H O D O N T I C S
CASE HISTORY REPORT
ABSTRACT
Langerhans cell histiocytosis (LCH) is a
childhood pathology with a peak of inci-
dence ranging from 1 to 4 years of age,
though diagnosis is often made in adult
age. LCH is clinically classified into three
types: eosinophilic granuloma, Hand–
Schuller–Christian disease and Abt–
Letterer–Siwe disease. We report a case
of Hand–Schüller–Christian disease with
diabetes insipidus, skull and maxillary
involvement in a 16-year-old boy referred
to our observation for gradual increase in
mobility of the teeth and subsequent
gradual loss of the second premolars and
the first molars of the upper jaw. Due to
the extension of the lesion and the age of
the patient, surgery, and chemotherapy
was chosen as the more fit treatment
according to the current protocol. The
clinical and radiological evaluation at the
end of the therapy and after 5 years
showed complete remission. The
absence of relapse has allowed to initiate
a fixed orthodontic dental alignment
treatment with a good response to ortho-
dontic treatment despite the underlying
disease. The present case exemplifies
the importance of close multidisciplinary
dental and medical collaboration includ-
ing general dentistry, periodontology,
oral medicine, oral and maxillofacial
pathology, oral radiology, orthodon-
tics and hematology-oncology for
diagnosis, management, treatment moni-
toring, and decision-making.
KEY WORDS: Langerhans cell
histiocytosis, LCH, eosinophilic
granuloma, Hand–Schüller–Christian
© 2018 Special Care Dentistry Association and Wiley Periodicals, Inc.
DOI: 10.1111/scd.12273
scd12273.indd 1
Multidisciplinary approach in a case of
Hand–Schüller–Christian disease with
maxillary involvement
Angela Pia Cazzolla, DDS, PhD;1 Nunzio Francesco Testa, MD, DDS;1
Gianfranco Favia, MD, DDS, PhD;1 Maria Grazia Lacaita, MD, DDS;1
Domenico Ciavarella, DDS;2 Khrystyna Zhurakivska, DDS;2* Giuseppe
Troiano, DDS;2 Lorenzo Lo Muzio, MD, DMD, PhD2
1Clinicof Dentistry, University of Bari, Bari, Italy; 2Department of Clinical and Experimental Medicine,
University of Foggia, Foggia, Italy.
*Corresponding author e-mail: khrystyna.zhurakivska@gmail.com
Spec Care Dentist XX(X): 1-5, 2017
Introd uct ion
Langerhans cell histiocytosis (LCH) is an idiopathic disease, characterized by a disor-
der of the reticulo-endothelial system in the human body. According to WHO/
Histiocyte Society,1 histiocytosis are classified into four classes: class I or LCH, which
are dendritic cells-related disorders, class II which includes macrophage-related disor-
ders, class III which encompasses malignant histiocyte disorders and class IV, to which
other rare diseases such as Rosai-Dorfman disease or sinus histiocytosis with massive
lymphadenopathy are attributed.2,3
Langherans cell histiocytosis (LCH) is ized by solitary lesions in a single organ
the main considerable disease among den- or by disseminated disease with organ
dritic cell-related disorders and it refers to dysfunction.2,4
a large group of diseases including eosino- The most commonly affected sites are
philic granuloma, Hand–Schuller–Cristian the bones, skin, and lymph nodes but the
disease, Letterer-Siwe disease, Hashimoto- lungs, the liver, the spleen and the
Pritker disease, self-healing histiocytosis, hematopoietic tissue might be
pure cutaneous histiocytosis, Langerhans’ involved.2,4,5 Bone is the most common
cell granulomatosis, Type II histiocytosis, organ affected by LCH. The most fre-
and the generic term nonlipidic reticu- quent sites of the osseous lesions of LCH
loendotheliosis.4,5 are the skull, femur, mandible, pelvis,
Its incidence among children ranges and spine. The disease may resolve spon-
from three to four cases per million per taneously or progress and compromise
year, with a predominance in males.5 The the function of vital organs, with severe
peak of incidence is recorded in the age and fatal consequences.2,4,5,7,8
between 1 and 4 years,6,7 thought diag- Localized disease is described as
nosis is often made in adult as a likely eosinophilic granuloma, while multisys-
evolution of juvenile form.4,5 tem forms of LCH have eponymous
LCH has a different clinical presenta- descriptions such as Hand–Schüller–
tion. Virtually, all tissues can be affected Christian disease, Letterer–Siwe disease,
by the disease, which may be character- and systemic LCH.9
Spec Care Dentist XX(X) 2018 1
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 L C H O F T H E M A X I L L A E . T R E AT M E N T A N D O RT H O D O N T I C S
This study reports a case of Hand—
Schüller–Christian disease with diabetes
insipidus, skull and maxillary involve-
ment in a young patient treated by
chemotherapy and surgery. The evalua-
tion at the end of therapy and after 5
years is presented. The absence of relapse
has allowed to initiate a fixed orthodon-
tic dental alignment treatment with a
good response to orthodontic treatment
despite the underlying disease.
Clinical case presentation
A 16-year-old male patient came to our
observation in October 2005 in Clinic of
Dentistry, University of Bari-Italy. The
patient reported a substantial mobility of
the upper second premolars and the first
molars (i.e., 15, 16, 25, and 26 according
to FDI World Dental Federation nota-
tion) that were subsequently lost. No
history of trauma and no association of
pain and swelling were reported.
On extraoral examination, the patient
presented brachycephalic skull, with
frontal bossing and slight hypertelorism.
On intraoral examination, the gingiva
was erythematous and edematous in the
posterior region of the upper jaw.
Gingival recession was present on the
upper right and left first premolars.
Grade I mobility was present on the
upper first premolars and second molars.
Gingival and plaque indexes according to
Loë10 were both 2.
Regarding systemic health, only a
problem of frequent urination was
referred.
The complete urine examination
(urine and plasma osmolality, water dep-
rivation test) revealed low specific
gravity (1,002) and daily urine output
was about 3.2 l/day.
Lateral and postero-anterior skull
radiograph revealed multiple well defined
punched out radiolucencies (Figures 1,2)
while the orthopantomograph revealed
bilateral irregular bone destruction in
relation to the premolar and first molars
region and periapical unspecified radi-
otransparency of the second molars (i.e.,
17 and 27; Figure 3).
Laboratory studies (complete blood
cell count, hematocrit, hemoglobin,
2 Spec Care Dentist XX(X) 2018
scd12273.indd 2
Figure 1. Lateral skull radiograph reveals
multiple well defined punched out radiolucen-
cies.
coagulation studies, liver function tests)
were normal and chest radiography, bone
scintigraphy showed no evidence of
other lesions.
The incisional biopsy of the mucosa
and that of the intra-osseous tissue in the
involved upper premolar and molar
regions was performed. Histopathologic
examination revealed a diffuse
Figure 2. Postero-anterior skull radiograph
reveals multiple well defined punched out
radiolucencies.
L C H o f t h e m a x i l l a e . Tr e a t m e n t a n d o r t h o d o n t i c s
Figure 3. Orthopantomograph: irregular bone
destruction in relation to 15, 16, 25, 26, and
periapical reactions of 17 and 27.
infiltration of large pale-staining histio-
cytic cells interspaced with lymphocytes,
plasma cells, and eosinophiles suggestive
of LCH (Figure 4a, b, c)
The treatment consisted of localized
lesion enucleation and bone curettage.
Postoperatively, patient was treated with
vinblastine (VBL) 6 mg/m2/weekly i.v.
bolus q 6 weeks and prednisone (PRD)
40 mg/m2/day x 4 weeks, tapering in 2
weeks. The evaluation at week 6 showed
nonactive disease. The treatment was
continued with VBL 6 mg/m2/weekly q 3
weeks and PRD 40 mg/m2/day x 5 days
q 3 weeks. The overall therapy duration
was 6 months.
Intranasal administration of 20 μg/
day of DDAVP (1-deamino-8-D-arginine
vasopressin), a long-acting vasopressin
analog, has been prescripted to reduce
the daily urinary volume.
Combined to systemic therapy, an
individual oral hygiene program stressing
the importance of the correct use of
toothbrush, dental floss, interdental
brushes, and of 0.2% chlorhexidine
mouth rinsing to obtain the best possible
control of plaque was suggested to the
patient. Considered the presence of
plaque, tartar and gingival pockets in
some points, a causal periodontal treat-
ment with supragingival and subgingival
scaling was performed in order to elimi-
nate any source of inflammation.
The clinical and radiological evalua-
tion at the end of the therapy showed
complete remission of the lesions
(Figure 5) and improvement of the oral
and periodontal condition was confirmed
by a significant clinical reduction of
plaque and gingivitis. During an
18-month follow-up period, frequent oral
examinations and appropriate dental
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 L C H O F T H E M A X I L L A E . T R E AT M E N T A N D O RT H O D O N T I C S
Figure 4. (a) hematoxylin and eosin stain (original magnification × 10); (b) hematoxylin and eosin stain (original magnification × 400): shows histiocytes
with large foaming cytoplasm; (c) Immunohistochemical stain for Langerhans cell-specific CD1a antigen showing strong positive staining of neoplastic
cells.
Figure 5. Orthopantomograph evaluation at the
end of the therapy shows complete remission.
interventions confirmed lack of LCH
recurrence and stabilization of periodon-
tal tissues.
At 5 years follow-up visit, no signs of
recurrence were detected. (Figure 6). The
absence of relapse allowed us to start a
fixed orthodontic dental alignment treat-
ment. Lateral cephalometric radiogram
and Roth-Jarabak cephalometric analysis
revealed protrusion of both jaws (SNA
angle: 86°, SNB angle: 84°), skeletal class
I occlusion (ANB angle: 2°), and a
normal dental overbite. The patient pro-
vided informed consent for diagnostic
and therapeutic procedures and possible
Figure 6. Orthopantomograph evaluation after
5 years.
Angela Pia et al. Spec Care Dentist XX(X) 2018 3
scd12273.indd 3
Figure 7. Fixed orthodontic dental alignment treatment.
use of biologic samples for research pur-
poses. Subsequently, orthodontic
treatment with the Straight Wire tech-
nique was performed, using brackets and
round nickel-titanium wires with small
diameter for the application of light force
(Figure 7). The orthodontic treatment
lasted about 2 years and, at the end,
retainers on both the upper and lower
jaws were applied to hold tooth position.
The 2-year follow-up showed a good
response to orthodontic treatment
despite the underlying disease.
Di sc us s ion
LCH, formerly called histiocytosis X
results from the clonal proliferation of
immunophenotypically and functionally
immature, morphologically rounded LCH
cells along with eosinophils, mac-
rophages, lymphocytes, and occasionally,
multinucleated giant cells.11 The term
LCH cells is used because there are clear
morphologic, phenotypic, and gene
expression similarities between
Langerhans cells of the epidermis (LCs)
and those in LCH lesions (LCH cells).
Historically, histiocytosis X was classified
into three distinct clinical forms: (1)
single or multiple bone lesions with no
visceral involvement (eosinophilic granu-
loma); (2) a chronic disseminated form
(Hand–Schüller–Christian disease) that
includes a classic triad of skull lesions,
exophthalmos, and diabetes insipidus;
and (3) an acute disseminated form
(Letterer-Siwe disease) that affects multi-
ple organs and has a poor prognosis.11
According to clinical classification of
the LCH study group which provides sig-
nificant information concerning the
treatment chosen on the basis of the
number of sites involved and the associ-
ated risk, the following forms can be
distinguished:
• Single System LCH (SS-LCH): if one
organ/system is involved, particularly
bones (unifocal or multifocal) and
lungs in adults;
• Multisystem LCH (MS- LCH): involv-
ing. two or more organs/systems, and
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 L C H O F T H E M A X I L L A E . T R E AT M E N T A N D O RT H O D O N T I C S
certain localizations are known as
“risk organs” (RO), including the
hematopoietic system, spleen, and
liver, because they present less
favorable prognoses
Systemic involvement of certain
organs affects negatively the prognosis.
In fact, if high-risk organs (liver, spleen,
bone marrow, and lungs) are involved,
mortality ranges reaches 30–50%, in
comparison with a mortality risk of 10%
when these organs are not affected.9
The etiology of LCH remains
unknown: controversy exists regarding
whether the clonal proliferation of LCH
cells results from a malignant transforma-
tion or is the result of an immunologic
stimulus. There are some considerations
that suggest that LCH is caused by
immunologic deregulations, with the
resultant of accumulation of Langerhans’s
cells. It is assumed to be a deficiency of
T-suppressor lymphocytes with an
increased CD4:CD8 ratio. Recently it has
been shown that LCH represents a clonal
proliferation of cells speculating that
LCH may represent a neoplastic disor-
der.12 In support of the hypothesis that
LCH is a clonal neoplastic disorder,
recent discoveries have shown theV600E
mutation in the BRAF oncogene in LCH
cells, the same mutation found in other
tumor types.13,14 In addition, almost all
lesions show evidence of activated ERK
downstream of BRAF. In all the lesions, it
was found that the extracellular signal-
related (ERK) pathway is activated,
including cases BRAF V600E-negative.
This leads one to suspect that there are
other mutations of the chain Ras-Raf-
MEK-ERK pathway.13,15,16
Pathologic histiocytes have abundant
pink cytoplasm, a deep groove in the
nucleus that gives them a coffee bean–
like appearance, and positive
immunohistochemical staining for CD1a,
S100, and CD207.
Children and adults show different
patterns of involvement. Pulmonary dis-
ease either in multifocal or isolated LCH
is very frequent in adults and infrequent
or rare in children. Diabetes insipidus
and skin involvement is found frequently
both in children and adults, while bone
lesions are more frequent in children
4 Spec Care Dentist XX(X) 2018
scd12273.indd 4
than in adults,4,7 involving the jaws in
30% of cases.14 Involvement of facial
bones is frequently associated with soft
tissue swelling, tenderness, and facial
asymmetry. Skull is the most common
site involved in children and 50% of
cases report diabetes insipidus associ-
ated.9 HSC is primarily seen in children
and it is rarely seen in adults. HSC has
an incidence of 0.18/1,00,000 with
approximately 30% of cases occurring in
adult. The classical triad of HSC disease:
exophthalmos, diabetes insipidus, and
calvarial lytic lesions–is seen only in one-
third of patients.15
Diabetes insipidus (DI) is the most
common disease-related consequence
that can predate the diagnosis or develop
anytime during the course of the dis-
ease16 Polyuria and polydipsia, and/or
structural abnormalities of the hypo-
thalamo-pituitary region dictate
investigations to confirm DI.
Oral manifestations are the earliest
signs in around 5% to 75% of patients.
These include sore mouth, halitosis, gin-
givitis, unpleasant taste, loose teeth, and
failure of extracted tooth sockets to heal.
Loss of supporting bone mimics
advanced periodontal disease.17
The course of this disease is entirely
variable; in 35% of patients, it is compat-
ible with the life, while in 15% of
patients, it is fatal.7,18
The choice of treatment, topical or
systemic, takes into account the site and
extent of the disease. Guide protocols for
the treatment of patients with LCH are
defined by international multicenter clini-
cal studies, LCH I-III, and are being
developed by the LCH-IV trial. Unifocal
bone lesions are the predominant clinical
form of LCH. The choice of approach
should take account of the symptoms, the
organ affected, and the size of the lesion.
Localized oral lesions may be treated
by surgical curettage or excision, intrale-
sional corticosteroids injection or a low
dose regimen of systemic oral corticoster-
oids (e.g., prednisolone 20 to 30 mg/day
for 2–4 week and then followed by taper-
ing of the dose). Radiation is an alternative
procedure for localized bone lesions.18
Multisystemic disease needs systemic
chemotherapy. The most common agents
L C H o f t h e m a x i l l a e . Tr e a t m e n t a n d o r t h o d o n t i c s
used in different combination regimens
and several cycles are corticosteroids,
vinblastine, etoposide, cytarabine, 6-mer-
capto purine, methotrexate,
2-chlorodeoxyadenosine, cyclosporine,
thalidomide and others.19,20
Other therapies include supervoltage
therapy, supportive therapy, control of
diabetic insipidus and surgery in specific
indications.18,20
In this case, considering that multiple
lesions affecting bones of the skull-facial
region may be at high risk of squeal, a sys-
temic chemotherapy treatment was
chosen, in addition to surgical excision
surgery.21 A treatment with vinblastine and
prednisone for 6 months was programmed,
considering that such drug association
demonstrated better results when com-
pared to a single-agent therapy.22
Although the LCH-III standards rec-
ommended an increasing of treatment
duration from 6 to 12 months for
patients with high-risk LCH, an accurate
surgical enucleation and a good response
to the systemic therapy resulted in non-
active disease at week 6, made us to opt
for the shorter duration of therapy, like
in LCH-II protocol.21
Given a high risk of reactivation and
the choice of a shorter therapy cycle, a
careful and frequent follow-up visits were
essential.23
Only after 5 years of follow-up with
no signs of relapse, an orthodontic treat-
ment was programmed.
Our experience, though limited to a
single case, confirms the effectiveness of
the therapy established by the current
guidelines. Even if a 6 months therapy
has been considered appropriate in this
case, we agree that an increased treat-
ment duration is appropriate.
The results of the new LCH-IV trial
will provide new and more precise infor-
mation in order to determine optimal
therapy for all LCH patients.
C oncl us ions
A close multidisciplinary dental and
medical collaboration with oral
radiologist, hematologist and oncologist
was implemented in order to establish
diagnosis, management, treatment
31/01/18 9:42 PM
 L C H O F T H E M A X I L L A E . T R E AT M E N T A N D O RT H O D O N T I C S
monitoring, and decision-making. Due to
the characteristic presence of osteolytic
lesions of the cranium (subsequently his-
topathologically confirmed LCH origin),
diabetes insipidus, associated with brach-
ycephalic skull, with frontal bossing and
slight hypertelorism, the diagnosis of
Hand—Schüller–Christian was defined.
Our approach, in accord with the
general recommendations, allowed us to
obtain a complete remission and a stable
result, as confirmed by the follow-up
exams. Furthermore, thanks to a multi-
disciplinary approach, also the
stomatologic problems, including the
malocclusion and periodontal status were
treated. A careful orthodontic treatment
allowed to limit the aesthetic and func-
tional discomfort stemmed from the
consequences of the disease.
D i s claim er state me nt
Nothing to declare.
C on tr ib u tor s
C.A.P. and Z.K. carried out the clinical
study of the case and drafted the manu-
script. C.D. performed the therapy. T.N.F.
has been involved in analysis and inter-
pretation of data. L.M.G. gave technical
support and conceptual advice. F.G. con-
ceived the study and participated in the
coordination of the treatment. T.G. and
L.M.L. reviewed the article critically for
important intellectual content. All authors
read and approved the final manuscript.
F un din g
This research received no specific grant
from any funding agency in the public,
commercial, or not-for-profit.
D eclar ation o f i nte re st
In accordance with publisher policy and
their ethical obligation the authors
declare that there are no conflicts-of-
interest related to the publication of this
manuscript.
E t hics appr oval
Ethics approval is not required because
this is a report of a single case not
Angela Pia et al. Spec Care Dentist XX(X) 2018 5
scd12273.indd 5
including private information such as
patient’s identification and face photos.
Written informed consent was obtained
from the patient’s legal guardian(s) for
publication of this case report and any
accompanying images. A copy of the
written consent is available for review by
the Editor-in-Chief of this journal.
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