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\begin{document}

\title{LANGERHANS CELL HISTIOCYTOSIS IN A PEDIATRIC PATIENT: A TYPICAL
PRESENTATION WITH ORAL MANIFESTATIONS}



\author[1]{Royasa Shakya}%
\author[1]{Bandana Koirala}%
\author[1]{Ashok Dongol}%
\author[1]{Iccha Maharjan}%
\author[1]{Shashi Keshwar}%
\author[1]{Neetu Jain}%
\author[1]{Ashish Shrestha}%
\affil[1]{BP Koirala Institute of Health Sciences}%


\vspace{-1em}



  
  \date{May 16, 2024}


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\textbf{Introduction}

Langerhans cell histiocytosis (LCH) is a rare hematological disorder
characterized by intense and abnormal proliferation of bone
marrow-derived immature myeloid dendritic cells; Langerhans cells (LCs)
in the skin, bone, lymph nodes, and other
organs.\textsuperscript{1}Although, due to its low occurrence, limited
information on the epidemiology of LCH is available, an estimated 5 to 9
cases per million in children \textless{} 15 years of age, and 1 case
per million in patients \textgreater{} 15 years of age have been
reported.\textsuperscript{2}

Depending on the different clinical manifestations, LCH had been
classified conventionally by the International Histiocyte Society into
three different types: Type I - Eosinophilic granuloma (chronic focal
LCH), Type II - Hand-Sch\selectlanguage{ngerman}üller-Christian disease (chronic disseminated
LCH) and Type III - Letterer-Siwe disease (acute disseminated
LCH).\textsuperscript{3} However, because clinical findings are widely
manifested, the disease has also been classified into unifocal and
multifocal forms; depending on the extent of its spread throughout the
body. The unifocal form presents only one destructive lesion in an
organ, affecting bones or skin (80\% of cases), liver, spleen, brain,
and lymph nodes more frequently\textsuperscript{3} The disease manifests
itself in a variety of ways, from isolated disease that resolves on its
own to life-threatening multisystem disease, with a 20\% mortality
rate.\textsuperscript{4}

The involvement of head and neck region is quite common in LCH,
particularly the bones of skull and jaws. The oral soft tissue lesions
are also common and are mostly seen on the hard palate and gingiva.
Since the symptoms of LCH may first appear in the oral cavity before
occurring elsewhere in the body, a thorough knowledge of the clinical
presentation of the disease is important.\textsuperscript{1}

Awareness among clinicians regarding the clinical, histological, and
immune-histopathological features of the disease will help in early
diagnosis and treatment for better prognosis. Thus, this report aims to
present a case of Langerhans cell histiocytosis with the oral and dermal
manifestations seen in a pediatric patient.

\textbf{Case report}

A five-year-old male presented with a chief complain of loose teeth
bilaterally in the lower jaw since three months. On evaluation of the
history, the parents summarized that the child first complained of pain
while eating and occasional bleeding from gingiva six months back. Soon
the parents also noticed swelling and structural distortion in the
fingernails on left hand along with pus discharge from left ear. The
parents also added that they had brought the child for check-up six
months earlier but due to Covid-19 pandemic, no active intervention was
possible.

On clinical examination, there was blackish discoloration and
destruction of nail plate of middle and little finger of right hand and
all the fingers of left hand (Figure 3). Also, watery discharge was seen
from the left ear.

On intraoral examination, multiple ulcerations were present bilaterally
on hard palate, extending posteriorly with the largest lesion measuring
1.5 X 1 cm\textsuperscript{2} in maximum dimension (Figure 1a). After
six weeks, the ulcer showed central area of creamish white slough of
variable thickness with erythematous periphery (Figure 1b). On further
examination, Grade III mobility was present in relation to teeth 74 and
84 with gingival recession and grade II mobility were evident on 75 and
85. Also, the marginal and attached gingiva in relation to 75 and 85 was
inflamed (Figure 2).

Panoramic radiograph was advised, however, the image was distorted as
the patient was uncooperative. Interdental bone loss in relation to 64,
65, 74, 75, 84, and 85 teeth region with distortion of follicle of tooth
34 was observed.

Computer tomography (CT) scan of the head and neck region was performed
under midazolam sedation which showed mild soft tissue thickening in the
bilateral lateral aspect of hard palate. However, no obvious growth or
erosion of palate was observed.

The blood investigation showed elevated level of alkaline phosphate (387
U/L) (normal range: 35-130 U/L) and serum glutamic-oxaloacetic
transaminase (SGOT: 51 U/L) (normal range: 10-35 U/L). Also, there was
slight increase in serum glutamic-pyruvic transaminase (SGPT: 47 U/L)
(normal range: 09-43 U/L) and platelet (475000 cell/mm) (normal range:
150000-400000 cells/mm).

The clinical diagnosis of granulomatous disease was suggested and
incisional biopsy was planned under general anesthesia. Two soft tissue
specimens from hard palate and junction between hard and soft palate,
measuring 17 X 10 X 4 mm and 9 X 8 X 6 mm respectively were obtained,
fixed in 10\% neutral buffered formalin, and sent for routine
histopathological processing (Figure 4). The processed tissue were
embedded and sectioned into 3 \selectlanguage{greek}µ\selectlanguage{english}m sections and stained with routine
hematoxylin and eosin stain.

On histopathological examination a highly cellular connective tissue
stroma with numerous scattered round to polygonal shaped cells with pale
cytoplasm was evident (Figure 5a, 5b). On higher magnification (oil
immersion), a characteristic coffee bean shaped and oval nuclei which
were folded or indented with some cells having grooved nuclei were
observed (Figure 5c, 5d). Background stroma was abundant with
eosinophils (Figure 5d). Overlying epithelium was para to
non-keratinized stratified squamous type with irregular rete ridges. The
histopathological features along with clinical findings and altered
serum biochemical parameters were suggestive for Langerhans cell
histiocytosis as a probable diagnosis.

Further, on immune-histochemical analysis histiocytic cells showed
positivity to CD1a, Langerin (CD-207), and S-100 markers confirming the
diagnosis of LCH. 99MTC-MDP bone scan of the patient revealed normal
bone with no evidence of skeletal metastasis (Figure 6). Ultrasonography
of the upper abdomen and pelvic region showed normal scan with no spleen
and liver involvement.

A final diagnosis of Langerhans cell histiocytosis -- single system
multifocal disease was made and the patient underwent chemotherapy
(Vinblastine + Prednisolone) for 43 weeks. The lesions have healed and
no new lesions have developed in one year follow-up visit (Figure 7).

\textbf{Discussion}

Langerhans cell histiocytosis, formerly known as histiocytosis X, is a
term used to describe a group of clinico-pathological conditions marked
by a monoclonal proliferation of histiocyte-like cells followed by
varying numbers of eosinophils, lymphocytes, plasma cells, and
multinucleate giant cells on histological
examination.\textsuperscript{5} The histiocytes present here is
recognised as Langerhans cells. Langerhans cells are dendritic
mononuclear cells which are generally found in the epidermis, mucosa,
lymph nodes, and bone marrow. They generally present antigens to
T-lymphocytes; however literature review of LCH indicates that
Langerhans cells proliferate monoclonally, resulting in the destruction
of hard and soft tissues.\textsuperscript{6} Despite significant
progress in medical fields, the pathophysiology of LCH remains unclear;
suggested mechanisms are the product of either an abnormal autoimmune
response or a neoplastic process.\textsuperscript{4}

LCH can affect people of wide age range, but it is more common in
children under the age of 15 years, with a peak occurrence at 2--4 years
and a male predilection that is twice as high as that of
females.\textsuperscript{2} The present case was reported in a
five-year-old male child. The jaws are involved twice as commonly as the
oral soft tissues. The mandible is three times more frequently affected
than the maxilla with a higher predisposition for the posterior regions
of the jaws than the anterior regions.\textsuperscript{7} These findings
are similar to the present case where mandibular posterior regions were
affected more. In about 5\%-75\% of patients, oral manifestations are
the first signs and symptoms and sometimes the only symptom of LCH,
thus, prompting the patient to seek treatment from a
dentist.\textsuperscript{8} Eden P~et al., reported in a case series
(n=13) that seven of the cases showed intra-osseous lesion in the
posterior region of the jaw and oral mucosal involvement (tongue, buccal
mucosa and gingiva).\textsuperscript{9} Sore throat, halitosis,
gingivitis, gingival hypertrophy, unpleasant taste, tooth mobility with
alveolar expansion, jaw pain, facial swelling, mental nerve anaesthesia,
and inability of extracted tooth sockets to heal are some of the oral
symptoms. The loss of supporting alveolar bone may be mistaken for
advanced periodontitis.\textsuperscript{8} In the present case, palatal
ulcer, tooth mobility, pain, and bone loss were the features in
consideration.

According to Krooks et al., the involvement of nails is uncommon, but
can be seen as subungual pustules, hemorrhage, purpuric striae, purulent
discharge, longitudinal grooving, onycholysis, paronychia, and
pitting.\textsuperscript{4} In the present case as well, changes in the
nails were evident. LCH lacks the pathognomonic clinical or radiographic
features, thus, a definite diagnosis is based on a histologic and
immune-histochemical examination, where CD1a, Langerin (CD207), and
S-100 protein positivity is common.\textsuperscript{10} S-100 is a
calcium binding protein present in the nucleus and cytoplasm of glial
and schwann cells, melanocytes, chondrocytes, adipocytes and
myoepithelial cells and is positive for all tumors derived from these
cells. CD1a is expressed on Langerhans precursors, Langerhans cells and
thymic cortical T cells, whereas Langerin is a type II transmembrane
cell surface receptor produced by Langerhans cells which helps in
differentiating Langerhans cell histiocytosis from other non-Langerhans
cell histiocytic proliferations. As in our case immunostaining was
positive for CD1a, Langerin, and S-100, it helped in confirming the
diagnosis of LCH.

The dentists are usually the first clinicians to examine the child's
oral cavity, hence, awareness regarding the varied manifestations of
this rare condition is important for early diagnosis and appropriate
referral of the patient. Also, multidisciplinary approach is necessary
for the overall management and well-being of the child. Since, the
lesions present in LCH may be confounded with a malignant process,
histological and immune-histochemical tests play a vital role in
confirming the diagnosis.\textsuperscript{3}

Conclusion

Langerhans cell histiocytosis is a disease with a wide range of clinical
symptoms. LCH, being a rare condition, is at a high risk of being
misdiagnosed or underdiagnosed. A thorough history, clinical
examination, appropriate investigations and a sound knowledge of the
condition helps to make a correct diagnosis at an early stage, thus
reducing the morbidity and mortality associated with this pathology. An
interdisciplinary approach is also imperative for the success of the
management of the condition.

\textbf{Authorship list}\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
Author & Name & Nature of Work\tabularnewline
\midrule
\endhead
1. First Author & Dr. Royasa Shakya & Manuscript preparation and
confirmation\tabularnewline
2. Second Author & Dr. Bandana Koirala & Manuscript
editing\tabularnewline
3. Third Author & Dr. Ashok Dongol & Manuscript editing\tabularnewline
4. Fourth Author & Dr. Iccha Kumar Maharjan & Manuscript
editing\tabularnewline
5. Fifth Author & Dr. Shashi Keshwar & Manuscript editing\tabularnewline
6. Sixth Author & Dr. Neetu Jain & Manuscript editing\tabularnewline
7. Seventh Author (Corresponding Author) & Dr. Ashish Shrestha &
Manuscript preparation and confirmation\tabularnewline
\bottomrule
\end{longtable}

\textbf{Acknowledgement}

Dr. Sushma Gurung, Department of Pediatric Hematology and Oncology,
Bhaktapur Cancer Hospital, Nepal

\textbf{Conflict of Interest}

None

\textbf{References}

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diagnostic challenge in the oral cavity. \emph{Case Rep Pathol} .
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2. Difloe-Geisert JC, Bernauer SA, Schneeberger N, Bornstein MM, Walter
C. Periodontal manifestations of Langerhans cell histiocytosis: a
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doi:10.1007/s00784-021-03873-0

3. Ramos-Gutiérrez E, Alejo-González F, Ruiz-Rodríguez S,
Garrocho-Rangel JA, Pozos-Guillén A. Langerhans cell histiocytosis:
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4. Krooks J, Minkov M, Weatherall AG. Langerhans cell histiocytosis in
children: History, classification, pathobiology, clinical
manifestations, and prognosis. \emph{J Am Acad Dermatol} .
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5. Glick M, Feagans WM. \emph{Burket's Oral Medicine} . 12th ed.
People's Medical Publishing House-USA; 2015.

6. Rao DG, Trivedi MV, Havale R, Shrutha SP. A rare and unusual case
report of Langerhans cell histiocytosis. \emph{J oral Maxillofac Pathol}
. 2017;21(1):140-144. doi:10.4103/jomfp.JOMFP

7. Hicks J, Flaitz CM. Langerhans cell histiocytosis: Current insights
in a molecular age with emphasis on clinical oral and maxillofacial
pathology practice. \emph{Oral Surgery, Oral Med Oral Pathol Oral Radiol
Endodontology} . 2005;100(2 SUPPL.):42-66.
doi:10.1016/j.tripleo.2005.06.016

8. Bhargava D, Bhargava K, Hazarey V, Ganvir SM. Hand-Schüller-Christian
disease. \emph{Indian J Dent Res} . 2012;23(6):830-832.
doi:https://doi.org/10.4103/0970-9290.111273

9. Eden P, Abeyasinghe WA, Mufees MB, Jayasooriya PR. A series of 13 new
cases of langerhans cell histiocytosis of the oral cavity: A master of
disguise. \emph{Oral Heal Care} . 2017;2(1):1-4.
doi:10.15761/ohc.1000110

10. Dziegiel P, Doli\selectlanguage{polish}ń\selectlanguage{english}ska-Krajewska B, Duma\selectlanguage{polish}ń\selectlanguage{english}ska M, et al. Coexpression of
CD1a, langerin and Birbeck's granules in Langerhans cell histiocytoses
(LCH) in children: Ultrastructural and immunocytochemical
studies.\emph{Folia Histochem Cytobiol} . 2007;45(1):21-25.\selectlanguage{english}
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