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How to cite this article: Dina E, Escamilla Carpintero Y, Blazquez Mañá C M. Lymphoepithelial Carcinoma of the Nasal Cavity and Langerhans Cell
Histiocytosis: Two Synchronous Neoplasms. Glob J Oto, 2020; 23 (1): 556103 DOI: 10.19080/GJO.2020.23.556103
The authors report a case of a 78-year-old woman with two synchronous neoplasms: Langerhans cell histiocytosis and lymphoepithelial carcinoma of the nasal cavity. The histopathological findings are extremely rare and represent a challenge for the pathologist as the two malignancies coexist within the same tumoral tissue. A review of the literature is presented.
Malignant sinonasal tumors represent less than 1 % of human cancer and approximately 3% of all malignancies of the head and neck region, with an incidence of 1:100.000. LEC of the nasal cavity and paranasal sinuses has been recently accepted as a distinguishable entity which is topographically distinct, yet histologically like the NPC. Although they are both associated with EBV, there are reports of LEC EBV negative cases [1,2]. LCH is a rare proliferative disorder affecting 5-9:1000.000 children younger than 15 years of age and 5:1000.000 adults annually [3-5].
The patient was a 78-year-old woman without any known allergies, nonsmoker and who denied alcohol consumption. The medical history included auricular fibrillation, arterial hypertension, diabetes mellitus type II, hypothyroidism secondary to thyroidectomy for nodular goiter. A neurological impairment had appeared nine years previously, with dysarthria, ataxia, dysphagia for liquids with progressive worsening. The initial diagnosis was degenerative ataxia versus multiple system
atrophy. The patient rejected any medical treatment for this condition and attended on irregular basis rehabilitation sessions with the speech and swallow therapist. An important weight loss of 20kg had occurred for the last four years, with 6kg loss during the last six months.
The patient was referred to the hematology department for a 4cm right submandibular mass, indurated, non-tender, with gradual enlargement during the last year and with a fine needle aspiration cytology suggestive of LCH.
An adenectomy was performed and the result was metastatic adenopathy of nasopharyngeal carcinoma associated with reactive Langerhans cell proliferation. The patient was referred to the otolaryngology department. She did not present nasal complaints. Subsequent workup included physical exam, biopsy, and imaging. The head and neck examination showed multiple findings. Hypertrophy of the tail of the inferior turbinate and medial bulging of the lateral nasal wall in the inferior meatus were observed during endoscopy in the left nasal fossa. The macroscopic aspect of the nasal mucosa was normal. Biopsies taken from both sites were negative for malignity. The nasopharynx was normal.
Bulging of the left side of the hard palate was noted (Figure 1a)
in the oral cavity. The oral mucosa had normal aspect. The biopsy
from this mass was positive for lymphoepithelial carcinoma
associated with Langerhans histiocytosis. Reviewing the cervical
adenectomy, the same histopathological aspect was observed:
lymphoepithelial carcinoma intermingled with Langerhans cell
proliferation. Palpation assessment of the neck revealed multiple
cervical lymph nodes, the largest on the right side at level IIA.
PET/CT scan of the whole body was performed twice (initially and
four months later).
Head and neck imaging showed a hyperdense 18mm soft
tissue lesion at the tail of the left inferior turbinate (Figure 1b)
which also affected the left maxillary bone extending to the hard
palate with enlargement of the major palatine foramen and the
left pterygopalatine fossa. One hyperintense cervical lesion was
noted on the right side at level IIA of 3cm diameter and one on the
left side of 11mm at the same level (Figure 1b & 1c). On the second
scan the adenopathy enlarged to 3.5cm. The nasopharynx was
normal. Thorax imaging revealed multiple isolated pulmonary
nodules less than one centimeter bilateral, in the upper fields
without abnormal metabolism.
Abdominal and pelvic imaging: sclerotic lesion on the right
sacral ala of 3cm diameter with moderate metabolism (Figure
1e & 1f). This lesion remained stable. The patient rejected
the bone biopsy to rule out a distant metastasis. Serology for
Epstein-Barr virus was positive. The patient was evaluated by
the multidisciplinary head and neck cancer committee of the
authors’ institution and was staged as T4N2cM0/ T4N2cM1
(due to the sacral lesion) of LEC of nasal cavity and paranasal
sinuses associated with LCH (8th edition of TNM classification).
Both surgery and chemotherapy were discarded, palliative
radiotherapy was reserved in case of worsening of symptoms.
LEC consists of poorly differentiated squamous cell carcinoma
or histologically undifferentiated carcinoma accompanied by
abundant reactive infiltration of lymphocytes and plasmatic cells.
It is associated with EBV infection. However, there are EBV negative
cases reported in Europe and USA. The serology does not correlate
with the clinical prognose of the disease. It usually affects men
between 50-70 years of age. The nasal septum and nasal cavity are
the most affected sites. It is a radiosensitive neoplasm. Only 15%
of LEC cases presents with lymphadenopathy in comparison with
85% of NPC cases [2,6-8].
LEC is characterized by a submucosal neoplastic proliferation
associated by a nonneoplastic lymphoplasmacytic infiltrate (less
abundant than in NPC). Neoplastic cells have large round to oval
nuclei with one or more nucleoli and abundant amphophilic
cytoplasm. Nuclear polymorphism can be observed. The mitotic
activity usually is not increased. Neoplastic cells are cytokeratin
positive and usually the EBER staining is intensely positive. P16
staining, melanoma-related markers, hematolymphoid markers
and neuroendocrine/ neuroectoderm markers are absent .
Differential diagnosis of sinonasal LEC is made mainly
with the sinonasal undifferentiated carcinoma, non- Hodgkin
lymphoma and nasopharyngeal carcinoma. There are few cases
published of lymphoepithelial carcinoma of the nasal cavity and
the paranasal sinuses. Takakura et al. presented in 2018 a review
of the previously 9 reported cases of sinonasal lymphoepithelial
carcinoma between 1980-2018. There are only two case series
published with 33 patients registered: Zong et al.  20 patients
and Jeng et al.  13 patients. To avoid confusion, it is important
to mention that LEC was previously named nasopharyngeal-type
undifferentiated carcinoma of the nasal cavity and paranasal
Histiocytosis are disorders characterized by accumulation of
macrophages, dendritic cells, monocyte-derived cells in tissues
and organs. There are over 100 subtypes described. The revised
classification published by Emile et al.  in 2016 consists of
five groups: Langerhans-related, cutaneous and mucocutaneous,
malignant histiocytosis, Rosai-Dorfman disease, hemophagocytic
lymph histiocytosis and macrophage activation syndrome .
LCH is a clonal proliferation of CD1a+ and CD207+ cells. The
clonality itself does not imply a neoplastic process. The BRAF
V600E mutation discovered in more than half of the patients is
not specific for LCH but it is a neoplastic disease .
The diagnosis of LCH requires the detection of Langerhans cell
markers. Detection of CD1a and CD207 (langerina) expression has
replaced the detection of Birbeck granules and permits differential
pathological diagnosis with other entities like indeterminate
cell histiocytosis (CD207 immunostaining negative) and Rosai-
Dorfman disease. Langerhans cells are often accompanied by
eosinophils and multinucleated giant cells. Although the mitotic
activity might be high, the diagnosis of malignant histiocytosis
cannot be made in the absence of major nuclear atypia and clinical
evidence of rapid tumor progression .
Association between LCH and neoplasms has been reported.
Ma et al.  published in 2018 a case series of 132 consecutive
adult patients with LCH (1990-2015). One third of the patients
had another neoplastic disease: a solid tumor (74%), a lymphoma
(17%) or a hematologic malignancy (9%). The most frequent
solid tumor was lung cancer followed by breast and colorectal
cancer. Follicular and Hodgkin lymphoma were the most common
in the lymphoma group and acute myeloid leukemia was the most
common hematologic malignancy. Mutations within BRAF/ERK
genes and / or use of carcinogenic agents like etoposide may be
implicated in the tumor genesis .
The histopathologic examination of both biopsies is similar:
a unique pattern with clusters of lymphoepithelial carcinoma
consisting of epithelial cell nests and presence of abundant
histiocytic cells closely intermingled with epithelial component, as
a network encompassing epithelial cells (Figure 2). Carcinomatous
cells expressed immunohistochemical markers of squamous
origin (p40), negative expressions for p16 and intense and diffuse
nuclear pattern positivity for EBER. The histiocytic component
was positive for S-100 protein, CD1a and CD207, confirming the
diagnosis of Langerhans cell histiocytosis (Figure 3a & 3b).
Determination of the mutational status of the BRAF gene
was performed for both epithelial and histiocytic components,
confirming the presence of the V600E mutation of the BRAF in the
Langerhans cell component and not in the epithelial component
(Figure 4). This finding confirms two synchronous neoplasms
within the same tumor. The neurologic condition of the patient is
compatible with ND-LCH. This rare condition has miscellaneous
manifestations from subtle to serious neurologic impairment (e.g.
ataxia, spastic quadriparesis, intellectual disability, psychiatric
symptoms) . Characteristic brain MRI changes are described
for ND-LCH and elevated osteopontina in the cerebrospinal fluid
helps differentiating ND-LCH from other neurodegenerative
disorders [11,12] . Unfortunately, a complete study in the case
presented was not made. Nevertheless, the association between
the neurologic symptoms and the stable sacral bone lesion might
indicate a previous long standing LCH.
Further research is needed to clarify the relationship between
the LEC and the LCH (if one can induce the other or if there is a
common initial trigger for both malignancies). The clinical case
reported is exceedingly rare, probably the first reported till now.