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 Multidisciplinary approach in a case of

Langerhans cell histiocytosis (LCH) is a
childhood pathology with a peak of inci-
dence ranging from 1 to 4 years of age,
Hand–Schüller–Christian disease with
though diagnosis is often made in adult
age. LCH is clinically classified into three maxillary involvement
types: eosinophilic granuloma, Hand–
Schuller–Christian disease and Abt–
Letterer–Siwe disease. We report a case Angela Pia Cazzolla, DDS, PhD;1 Nunzio Francesco Testa, MD, DDS;1
of Hand–Schüller–Christian disease with Gianfranco Favia, MD, DDS, PhD;1 Maria Grazia Lacaita, MD, DDS;1
diabetes insipidus, skull and maxillary
Domenico Ciavarella, DDS;2 Khrystyna Zhurakivska, DDS;2* Giuseppe
involvement in a 16-year-old boy referred
to our observation for gradual increase in Troiano, DDS;2 Lorenzo Lo Muzio, MD, DMD, PhD2
mobility of the teeth and subsequent
1Clinicof Dentistry, University of Bari, Bari, Italy; 2Department of Clinical and Experimental Medicine,
gradual loss of the second premolars and
the first molars of the upper jaw. Due to University of Foggia, Foggia, Italy.
the extension of the lesion and the age of *Corresponding author e-mail: [email protected]
the patient, surgery, and chemotherapy
was chosen as the more fit treatment Spec Care Dentist XX(X): 1-5, 2017
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
Introd uct ion
Langerhans cell histiocytosis (LCH) is an idiopathic disease, characterized by a disor-
a fixed orthodontic dental alignment der of the reticulo-endothelial system in the human body. According to WHO/
treatment with a good response to ortho- Histiocyte Society,1 histiocytosis are classified into four classes: class I or LCH, which
dontic treatment despite the underlying are dendritic cells-related disorders, class II which includes macrophage-related disor-
disease. The present case exemplifies ders, class III which encompasses malignant histiocyte disorders and class IV, to which
the importance of close multidisciplinary other rare diseases such as Rosai-Dorfman disease or sinus histiocytosis with massive
dental and medical collaboration includ- lymphadenopathy are attributed.2,3
ing general dentistry, periodontology,
oral medicine, oral and maxillofacial
pathology, oral radiology, orthodon-
tics and hematology-oncology for Langherans cell histiocytosis (LCH) is ized by solitary lesions in a single organ
diagnosis, management, treatment moni- the main considerable disease among den- or by disseminated disease with organ
toring, and decision-making. dritic cell-related disorders and it refers to dysfunction.2,4
a large group of diseases including eosino- The most commonly affected sites are
KEY WORDS: Langerhans cell philic granuloma, Hand–Schuller–Cristian the bones, skin, and lymph nodes but the
histiocytosis, LCH, eosinophilic disease, Letterer-Siwe disease, Hashimoto- lungs, the liver, the spleen and the
granuloma, Hand–Schüller–Christian 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

© 2018 Special Care Dentistry Association and Wiley Periodicals, Inc.

DOI: 10.1111/scd.12273 Spec Care Dentist XX(X) 2018 1

scd12273.indd 1 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

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 Figure 3. Orthopantomograph: irregular bone
good response to orthodontic treatment destruction in relation to 15, 16, 25, 26, and
periapical reactions of 17 and 27.
despite the underlying disease.

infiltration of large pale-staining histio-

Clinical case presentation cytic cells interspaced with lymphocytes,
A 16-year-old male patient came to our plasma cells, and eosinophiles suggestive
observation in October 2005 in Clinic of of LCH (Figure 4a, b, c)
Dentistry, University of Bari-Italy. The The treatment consisted of localized
patient reported a substantial mobility of lesion enucleation and bone curettage.
the upper second premolars and the first Figure 1. Lateral skull radiograph reveals
Postoperatively, patient was treated with
molars (i.e., 15, 16, 25, and 26 according multiple well defined punched out radiolucen- vinblastine (VBL) 6 mg/m2/weekly i.v.
to FDI World Dental Federation nota- cies. bolus q 6 weeks and prednisone (PRD)
tion) that were subsequently lost. No 40 mg/m2/day x 4 weeks, tapering in 2
history of trauma and no association of coagulation studies, liver function tests) weeks. The evaluation at week 6 showed
pain and swelling were reported. were normal and chest radiography, bone nonactive disease. The treatment was
On extraoral examination, the patient scintigraphy showed no evidence of continued with VBL 6 mg/m2/weekly q 3
presented brachycephalic skull, with other lesions. weeks and PRD 40 mg/m2/day x 5 days
frontal bossing and slight hypertelorism. The incisional biopsy of the mucosa q 3 weeks. The overall therapy duration
On intraoral examination, the gingiva and that of the intra-osseous tissue in the was 6 months.
was erythematous and edematous in the involved upper premolar and molar Intranasal administration of 20 μg/
posterior region of the upper jaw. regions was performed. Histopathologic day of DDAVP (1-deamino-8-D-arginine
Gingival recession was present on the examination revealed a diffuse vasopressin), a long-acting vasopressin
upper right and left first premolars. analog, has been prescripted to reduce
Grade I mobility was present on the the daily urinary volume.
upper first premolars and second molars. Combined to systemic therapy, an
Gingival and plaque indexes according to individual oral hygiene program stressing
Loë10 were both 2. the importance of the correct use of
Regarding systemic health, only a toothbrush, dental floss, interdental
problem of frequent urination was brushes, and of 0.2% chlorhexidine
referred. mouth rinsing to obtain the best possible
The complete urine examination control of plaque was suggested to the
(urine and plasma osmolality, water dep- patient. Considered the presence of
rivation test) revealed low specific plaque, tartar and gingival pockets in
gravity (1,002) and daily urine output some points, a causal periodontal treat-
was about 3.2 l/day. ment with supragingival and subgingival
Lateral and postero-anterior skull scaling was performed in order to elimi-
radiograph revealed multiple well defined nate any source of inflammation.
punched out radiolucencies (Figures 1,2) The clinical and radiological evalua-
while the orthopantomograph revealed tion at the end of the therapy showed
bilateral irregular bone destruction in complete remission of the lesions
relation to the premolar and first molars (Figure 5) and improvement of the oral
region and periapical unspecified radi- and periodontal condition was confirmed
otransparency of the second molars (i.e., by a significant clinical reduction of
17 and 27; Figure 3). plaque and gingivitis. During an
Figure 2. Postero-anterior skull radiograph 18-month follow-up period, frequent oral
Laboratory studies (complete blood
reveals multiple well defined punched out examinations and appropriate dental
cell count, hematocrit, hemoglobin, radiolucencies.

2 Spec Care Dentist XX(X) 2018 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

scd12273.indd 2 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

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.

Figure 7. Fixed orthodontic dental alignment treatment.

interventions confirmed lack of LCH
recurrence and stabilization of periodon- use of biologic samples for research pur- Langerhans cells of the epidermis (LCs)
tal tissues. poses. Subsequently, orthodontic and those in LCH lesions (LCH cells).
At 5 years follow-up visit, no signs of treatment with the Straight Wire tech- Historically, histiocytosis X was classified
recurrence were detected. (Figure 6). The nique was performed, using brackets and into three distinct clinical forms: (1)
absence of relapse allowed us to start a round nickel-titanium wires with small single or multiple bone lesions with no
fixed orthodontic dental alignment treat- diameter for the application of light force visceral involvement (eosinophilic granu-
ment. Lateral cephalometric radiogram (Figure 7). The orthodontic treatment loma); (2) a chronic disseminated form
and Roth-Jarabak cephalometric analysis lasted about 2 years and, at the end, (Hand–Schüller–Christian disease) that
revealed protrusion of both jaws (SNA retainers on both the upper and lower includes a classic triad of skull lesions,
angle: 86°, SNB angle: 84°), skeletal class jaws were applied to hold tooth position. exophthalmos, and diabetes insipidus;
I occlusion (ANB angle: 2°), and a The 2-year follow-up showed a good and (3) an acute disseminated form
normal dental overbite. The patient pro- response to orthodontic treatment (Letterer-Siwe disease) that affects multi-
vided informed consent for diagnostic despite the underlying disease. ple organs and has a poor prognosis.11
and therapeutic procedures and possible According to clinical classification of
the LCH study group which provides sig-
Di sc us s ion nificant information concerning the
treatment chosen on the basis of the
LCH, formerly called histiocytosis X
number of sites involved and the associ-
results from the clonal proliferation of
ated risk, the following forms can be
immunophenotypically and functionally
distinguished:
immature, morphologically rounded LCH
cells along with eosinophils, mac- • Single System LCH (SS-LCH): if one
rophages, lymphocytes, and occasionally, organ/system is involved, particularly
multinucleated giant cells.11 The term bones (unifocal or multifocal) and
LCH cells is used because there are clear lungs in adults;
Figure 6. Orthopantomograph evaluation after morphologic, phenotypic, and gene • Multisystem LCH (MS- LCH): involv-
5 years. expression similarities between ing. two or more organs/systems, and

Angela Pia et al. Spec Care Dentist XX(X) 2018 3

scd12273.indd 3 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

certain localizations are known as than in adults,4,7 involving the jaws in used in different combination regimens
“risk organs” (RO), including the 30% of cases.14 Involvement of facial and several cycles are corticosteroids,
hematopoietic system, spleen, and bones is frequently associated with soft vinblastine, etoposide, cytarabine, 6-mer-
liver, because they present less tissue swelling, tenderness, and facial capto purine, methotrexate,
favorable prognoses asymmetry. Skull is the most common 2-chlorodeoxyadenosine, cyclosporine,
site involved in children and 50% of thalidomide and others.19,20
Systemic involvement of certain
cases report diabetes insipidus associ- Other therapies include supervoltage
organs affects negatively the prognosis.
ated.9 HSC is primarily seen in children therapy, supportive therapy, control of
In fact, if high-risk organs (liver, spleen,
and it is rarely seen in adults. HSC has diabetic insipidus and surgery in specific
bone marrow, and lungs) are involved,
an incidence of 0.18/1,00,000 with indications.18,20
mortality ranges reaches 30–50%, in
approximately 30% of cases occurring in In this case, considering that multiple
comparison with a mortality risk of 10%
adult. The classical triad of HSC disease: lesions affecting bones of the skull-facial
when these organs are not affected.9
exophthalmos, diabetes insipidus, and region may be at high risk of squeal, a sys-
The etiology of LCH remains
calvarial lytic lesions–is seen only in one- temic chemotherapy treatment was
unknown: controversy exists regarding
third of patients.15 chosen, in addition to surgical excision
whether the clonal proliferation of LCH
Diabetes insipidus (DI) is the most surgery.21 A treatment with vinblastine and
cells results from a malignant transforma-
common disease-related consequence prednisone for 6 months was programmed,
tion or is the result of an immunologic
that can predate the diagnosis or develop considering that such drug association
stimulus. There are some considerations
anytime during the course of the dis- demonstrated better results when com-
that suggest that LCH is caused by
ease16 Polyuria and polydipsia, and/or pared to a single-agent therapy.22
immunologic deregulations, with the
structural abnormalities of the hypo- Although the LCH-III standards rec-
resultant of accumulation of Langerhans’s
thalamo-pituitary region dictate ommended an increasing of treatment
cells. It is assumed to be a deficiency of
investigations to confirm DI. duration from 6 to 12 months for
T-suppressor lymphocytes with an
Oral manifestations are the earliest patients with high-risk LCH, an accurate
increased CD4:CD8 ratio. Recently it has
signs in around 5% to 75% of patients. surgical enucleation and a good response
been shown that LCH represents a clonal
These include sore mouth, halitosis, gin- to the systemic therapy resulted in non-
proliferation of cells speculating that
givitis, unpleasant taste, loose teeth, and active disease at week 6, made us to opt
LCH may represent a neoplastic disor-
failure of extracted tooth sockets to heal. for the shorter duration of therapy, like
der.12 In support of the hypothesis that
Loss of supporting bone mimics in LCH-II protocol.21
LCH is a clonal neoplastic disorder,
advanced periodontal disease.17 Given a high risk of reactivation and
recent discoveries have shown theV600E
The course of this disease is entirely the choice of a shorter therapy cycle, a
mutation in the BRAF oncogene in LCH careful and frequent follow-up visits were
cells, the same mutation found in other variable; in 35% of patients, it is compat-
ible with the life, while in 15% of essential.23
tumor types.13,14 In addition, almost all Only after 5 years of follow-up with
lesions show evidence of activated ERK patients, it is fatal.7,18
no signs of relapse, an orthodontic treat-
downstream of BRAF. In all the lesions, it The choice of treatment, topical or
ment was programmed.
was found that the extracellular signal- systemic, takes into account the site and
Our experience, though limited to a
related (ERK) pathway is activated, extent of the disease. Guide protocols for
single case, confirms the effectiveness of
including cases BRAF V600E-negative. the treatment of patients with LCH are
the therapy established by the current
This leads one to suspect that there are defined by international multicenter clini-
guidelines. Even if a 6 months therapy
other mutations of the chain Ras-Raf- cal studies, LCH I-III, and are being
has been considered appropriate in this
MEK-ERK pathway.13,15,16 developed by the LCH-IV trial. Unifocal
case, we agree that an increased treat-
Pathologic histiocytes have abundant bone lesions are the predominant clinical
ment duration is appropriate.
pink cytoplasm, a deep groove in the form of LCH. The choice of approach
The results of the new LCH-IV trial
nucleus that gives them a coffee bean– should take account of the symptoms, the
will provide new and more precise infor-
like appearance, and positive organ affected, and the size of the lesion.
mation in order to determine optimal
immunohistochemical staining for CD1a, Localized oral lesions may be treated
therapy for all LCH patients.
S100, and CD207. by surgical curettage or excision, intrale-
Children and adults show different sional corticosteroids injection or a low
patterns of involvement. Pulmonary dis- dose regimen of systemic oral corticoster-
ease either in multifocal or isolated LCH oids (e.g., prednisolone 20 to 30 mg/day C oncl us ions
is very frequent in adults and infrequent for 2–4 week and then followed by taper- A close multidisciplinary dental and
or rare in children. Diabetes insipidus ing of the dose). Radiation is an alternative medical collaboration with oral
and skin involvement is found frequently procedure for localized bone lesions.18 radiologist, hematologist and oncologist
both in children and adults, while bone Multisystemic disease needs systemic was implemented in order to establish
lesions are more frequent in children chemotherapy. The most common agents diagnosis, management, treatment

4 Spec Care Dentist XX(X) 2018 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

scd12273.indd 4 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 including private information such as 12. Putters TF, de Visscher JG, van Veen A,
the characteristic presence of osteolytic patient’s identification and face photos. Spijkervet FK. Intralesional infiltration of
lesions of the cranium (subsequently his- Written informed consent was obtained corticosteroids in the treatment of localised
topathologically confirmed LCH origin), from the patient’s legal guardian(s) for langerhans’ cell histiocytosis of the mandible
diabetes insipidus, associated with brach- publication of this case report and any Report of known cases and three new cases.
ycephalic skull, with frontal bossing and accompanying images. A copy of the Int J Oral Maxillofac Surg 2005;34(5):571-75.
slight hypertelorism, the diagnosis of written consent is available for review by 13. Cazzolla AP, Troiano G, Zhurakivska K, et al.
Hand—Schüller–Christian was defined. the Editor-in-Chief of this journal. Langerhans cell histiocytosis of the maxillae
Our approach, in accord with the in a child treated only with chemotherapy: a
general recommendations, allowed us to
obtain a complete remission and a stable
References case report. J Med Case Rep 2017;11(1):1-6.
14. Badalian-Very G, Vergilio JA, Fleming M,
1. Histiocytosis syndromes in children. Writing
result, as confirmed by the follow-up Rollins BJ. Pathogenesis of Langerhans cell
Group of the Histiocyte Society. Lancet
exams. Furthermore, thanks to a multi- histiocytosis. Annu Rev Pathol 2013;8:1-20.
1987;1(8526):208-9.
disciplinary approach, also the 15. Chakraborty R, Hampton OA, Shen X, et al.
2. Campos MK, Viana MB, de Oliveira BM,
stomatologic problems, including the Mutually exclusive recurrent somatic muta-
Ribeiro DD, Silva CM. Langerhans cell histi-
malocclusion and periodontal status were tions in MAP2K1 and BRAF support a
ocytosis: a 16-year experience. J Pediatr (Rio
treated. A careful orthodontic treatment central role for ERK activation in LCH
J) 2007;83(1):79-86.
allowed to limit the aesthetic and func- pathogenesis. Blood 2014;124(19):3007-15.
3. Favara BE, Feller AC, Pauli M, et al.
tional discomfort stemmed from the 16. Nelson DS, vanHalteren A, Quispel WT,
Contemporary classification of histiocytic dis-
consequences of the disease. et al. MAP2K1 and MAP3K1 mutations in
orders. The WHO Committee On Histiocytic/
Langerhans cell histiocytosis. Genes
Reticulum Cell Proliferations. Reclassification
D i s claim er state me nt Working Group of the Histiocyte Society. Med
Chromosomes Cancer 2015;54(6):361-8.
17. Bhargava D, Bhargava K, Hazarey V, Ganvir
Nothing to declare. Pediatr Oncol 1997;29(3):157-66.
4. Howarth DM, Gilchrist GS, Mullan BP, SM. Hand-Schuller-Christian disease. Indian
Wiseman GA, Edmonson JH, Schomberg PJ. J Dent Res 2012;23(6):830-2.
C on tr ib u tor s Langerhans cell histiocytosis: diagnosis, nat- 18. Garcia de Marcos JA, Dean Ferrer A,
C.A.P. and Z.K. carried out the clinical ural history, management, and outcome. Alamillos Granados F, et al. Langerhans cell
study of the case and drafted the manu- Cancer 1999;85(10):2278-90. histiocytosis in the maxillofacial area in
script. C.D. performed the therapy. T.N.F. 5. Muzzi L, Pini Prato GP, Ficarrat G. adults. Report of three cases. Med Oral Patol
has been involved in analysis and inter- Langerhans’ cell histiocytosis diagnosed Oral Cir Bucal 2007;12(2):E145-150.
pretation of data. L.M.G. gave technical through periodontal lesions: a case report. J 19. Arico M, Girschikofsky M, Genereau T, et al.
support and conceptual advice. F.G. con- Periodontol 2002;73(12):1528-33. Langerhans cell histiocytosis in adults. Report
ceived the study and participated in the 6. Glotzbecker MP, David F. Carpentieri, and from the International Registry of the
coordination of the treatment. T.G. and John P. Dormans. Langerhans cell histiocyto- Histiocyte Society. Eur J Cancer
L.M.L. reviewed the article critically for sis: clinical presentation, pathogenesis, and 2003;39(16):2341-48.
important intellectual content. All authors treatment from the LCH etiology. Univ Pa 20. Azariah ED, Chandrasekaran D,
read and approved the final manuscript. Orthop J 2002;15:67-73. Chinnaswami R, Balasubramaniam S, Jagdish
7. McClain KL. Langerhans cell histiocytosis: E. “Histiocytosis X” a rare case report. J Clin

F un din g what is the orphan telling us. Hematol

Am Soc Hematol Educ Program 2004:84-87.
Diagn Res 2016;10(10):ZD19-22.
21. Haupt R, Minkov M, Astigarraga I, et al.
This research received no specific grant Langerhans cell histiocytosis (LCH): guide-
8. Arico M, Egeler RM. Clinical aspects of
from any funding agency in the public, lines for diagnosis, clinical work-up, and
Langerhans cell histiocytosis. Hematol Oncol
commercial, or not-for-profit.
Clin North Am 1998;12(2):247-58. treatment for patients till the age of 18 years.
9. Lajolo C, Campisi G, Deli G, Littarru C, Pediatr Blood Cancer 2013;60(2):175-84.
D eclar ation o f i nte re st Guiglia R, Giuliani M. Langerhans’s cell his-
tiocytosis in old subjects: two rare case
22. Grois N, Prayer D, Prosch H, Minkov M,
Potschger U, Gadner H. Course and clinical
In accordance with publisher policy and
their ethical obligation the authors reports and review of the literature. impact of magnetic resonance imaging find-
declare that there are no conflicts-of- Gerodontology 2012;29(2):e1207-14. ings in diabetes insipidus associated with
interest related to the publication of this 10. Loe H. The Gingival Index, the Plaque Index Langerhans cell histiocytosis. Pediatr Blood
manuscript. and the Retention Index Systems. J Cancer 2004;43(1):59-65.
Periodontol 1967;38(6)(Suppl):610-16. 23. Minkov M, Steiner M, Potschger U, et al.
11. Lalitha C, Manjula M, Srikant K, Goyal S, Reactivations in multisystem Langerhans
E t hics appr oval Tanveer S. Hand schuller christian disease: a cell histiocytosis: data of the international
Ethics approval is not required because rare case report with oral manifestation. J LCH registry. J Pediatr 2008;153(5):700-5,
this is a report of a single case not Clin Diagn Res 2015;9(1):ZD28-30. 705 e701-702.

Angela Pia et al. Spec Care Dentist XX(X) 2018 5

scd12273.indd 5 31/01/18 9:42 PM