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\title{Primary cutaneous indeterminate cell histiocytosis following esophageal
cancer and followed by bullous pemphigoid: a case report from China}



\author[1]{Xiaoxiao Jia}%
\author[2]{Li-ling Shen}%
\author[2]{Lu Zhu}%
\affil[1]{zhejiang provincial institute of dermatology}%
\affil[2]{Zhejiang Provincial Dermatology Hospital}%


\vspace{-1em}



  
  \date{April 27, 2026}


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\selectlanguage{english}
\begin{abstract}
Indeterminate cell histiocytosis (ICH) is a rare histiocytic
proliferative disease with unknown etigo, which shared immunophenotypic
features of Langerhans cell and macrophages. ICH cells express CD1a,
S-100, and CD68 whereas langerin (CD207) is negative. This study
presents a case of a 75 -year-old man with varying sizes of some
scattered annular erythema over his chest, abdomen, limbs and 4 bullous
on the thigh for 1.5months. He had about 9 month's history of esophageal
cancer and treated with the radical radiotherapy treatment.
Histopathologic examination of his abdomen demonstrated accumulation of
mononuclear cells in the epidermis, infiltration of eosinophils and
lymphocytes in the dermal superficial layer. The histology of the
blister reported the formation of old subepidermal blister, slurry and
eosinophils in the blister as well as infiltration of eosinophils and
lymphocytes in the dermal superficial layer. Results of
immunohistochemistry identified positive for CD1a, S-100 and CD68 in
epidermal cells and dermal cells aggregation but negative for CD207.
However, the blisters and bullous were found over the lower limbs after
38 days. A diagnosis of bullous pemphigoid (BP) was arrived at according
to the examination of histopathology and direct immunofluorescent.
Therefore, that esophageal carcinoma, ICH, and BP lied in a single
patient, was found to be a rare case that deserved our considering of
the possible mechanism.%
\end{abstract}%



\sloppy


\textbf{Primary cutaneous indeterminate cell histiocytosis
followingesophageal~cancer and followed by bullous pemphigoid: a case
report from China}

Authors:

Xiaoxiao Jia\textsuperscript{1}

St 61 Wuyuan, Huzhou, Zhejiang, China.

Liling Shen\textsuperscript{1}

St 61 Wuyuan, Huzhou, Zhejiang, China.

Lu Zhu\textsuperscript{1}

St 61 Wuyuan, Huzhou, Zhejiang, China.

Affiliations:

Department of Dermatology, Zhejiang Provincial Institute of Dermatology

Correspondence:

Xiaoxiao Jia, Department of Dermatology, Zhejiang Provincial Institute
of Dermatology

St 61 Wuyuan, Huzhou, Zhejiang 313200, China.

E-mail:\emph{15088791481@163.com}

\textbf{Abstract}

\textbf{Introduction:} Indeterminate cell histiocytosis (ICH) is a rare
histiocytic proliferative disease with unknown etigo, which shared
immunophenotypic features of Langerhans cell and macrophages. There is a
relationship between ICH and cancer, especially on the hematopoietic
malignancy and follicular lymphoma.

\textbf{Case report:} This study presents a case of a 75 -year-old man
with varying sizes of some scattered annular erythema over his chest,
abdomen, limbs and 4 bullous on the thigh for 1.5months. He had about 9
month's history of esophageal cancer and treated with the radical
radiotherapy treatment. Histopathologic examination of his abdomen
demonstrated accumulation of mononuclear cells in the epidermis,
infiltration of eosinophils and lymphocytes in the dermal superficial
layer. The histology of the blister reported the formation of old
subepidermal blister, slurry and eosinophils in the blister as well as
infiltration of eosinophils and lymphocytes in the dermal superficial
layer. Results of immunohistochemistry identified positive for CD1a,
S-100 and CD68 in epidermal cells and dermal cells aggregation but
negative for CD207. However, the blisters and bullous were found over
the lower limbs after 38 days. A diagnosis of bullous pemphigoid (BP)
was arrived at according to the examination of histopathology and direct
immunofluorescent. He did not agree to the treatment for BP as advised
and died of multiple organ failure.

\textbf{Conclusions:} We hereby report the case of a patient with
primary cutaneous ICH who had been diagnosed of esophageal~cancer and
treated with the radical radiotherapy several months ago, followed by
BP. The association of ICH, esophageal~cancer and BP has not been
previously reported and the nature of the relationship among the
disorders remains to be established.

\textbf{KEY WORDS}

case report, indeterminate cell histiocytosis, cancer, bullous
pemphigoid

\textbf{Introduction}

Indeterminate cell histiocytosis (ICH) is a rare histiocytic
proliferative disease, which was first described by Wood \emph{et al.}in
1985. It predominantly affects adults with no gender predilection.
Further, its pathogenesis remained unknown, and presents as solitary or
generalized lesions \textsuperscript{{[}1{]}}. Solitary or multiple
papules and/or nodules which usually runs a benign process are the
general presentation of ICH. Diagnosis of ICH is based on the clinical
features, immunophenotype and histopathology. There is a relationship
between ICH and cancer, especially on the hematopoietic malignancy and
follicular lymphoma \textsuperscript{{[}2{]}}. In this study we report a
case of cutaneous indeterminate cell histiocytosis following esophageal
carcinoma and followed by bullous pemphigoid.

\textbf{Case report}

A man aged 75 years was presented with a 1.5 months history of some
scattered annular erythema and itching on his chest, abdomen and limbs
(Fig. 1). The lesions, in different sizes, increased in number gradually
and did not disappear during the period. Moreover, 4 bullous were
observed on thigh of the patient (Fig. 1C, 1D). Nine months prior to
presentation at our department, the patient had been diagnosed as
esophageal cancer in other hospital and treated with the radical
radiotherapy treatment. Currently, the treatment has been completed. It
was noted that, there was no history of such conditions in family of the
patient. Skin biopsy specimens were taken from the lesion of abdomen and
the blister of thigh. Histopathologic examination in abdomen
demonstrated accumulation of mononuclear cells in the epidermis,
infiltration of eosinophils and lymphocytes in the dermal superficial
layer (Fig. 2A). Immunohistochemical examination showed positive
expressing of CD1a, S-100 and CD68 in epidermal cells and dermal cells
aggregation, the expression of CD3, CD4, CD8, CD45RO as well as partly
expression of CD5, CD7, CD20 and CD79a. The specimen was negative for
CD207/Langerin (Fig. 3), CD56 and Ki-67. The histology of the blister
reported the formation of old subepidermal blister, the slurry and
eosinophils in the blister and infiltration of eosinophils and
lymphocytes in the dermal superficial layer (Fig. 2B).
Immunohistochemical study also showed that the histiocytes in epidermis
and dermis co-expressed CD1a, S-100 and CD68 marker, but were negative
for CD207/Langerin. They were also CD3, CD4, CD8, CD45RO, CD5, and
CD7positive. Diagnosis of indeterminate cell histiocytosis was hence
made based on these findings. Medical tests, such as routine laboratory
tests, a bone marrow biopsy and computed tomographic (CT) scan, did not
indicate any evidence of abnormality in other systems. He received
symptomatic treatment with intravenous drip of Compound Glycyrrhizin,
oral antihistamine (Medaclloratadine), topical Halometasone cream and
humectant in the Department of Dermatology and was discharged due to a
slight improvement in his condition a week later. However, 38 days
later, the patient was presented at our dermatology clinic again for the
blisters and bullous on the lower limbs (Fig. 4A). Histopathologic
examination revealed the subepidermal blister and the infiltration of a
large number of eosinophil in the blister and the dermis under the
blister. Direct immunofluorescent (DIF) showed that IgG deposited in the
basal membrane zone and IgM, IgA and C3 were negative (Fig. 4C). A
diagnosis of bullous pemphigoid (BP) was hence made based on
histopathologic examination and direct immunofluorescent. He was advised
the treatment of Corticosteroid for BP and informed about possible side
effects. The patient did not receive treatment for BP as advised. The
patient had died of multiple organ failure about eight months from a
telephone follow-up.

\textbf{Discussion}

Indeterminate cell histiocytosis owns both Langerhans cell and
non-Langerhans cell immunophenotypic features with CD1a, S-100 and CD68
positive as well as CD207 negative. Our study showed that the
histiocytes in epidermis and dermis co-expressed CD1a, S-100 and CD68
marker, but were negative for CD207/Langerin in dermis. The
CD207/Langerin was involved in formation of Birbeck and its expression
could be a sign of Langerhans cells. Therefore, a diagnosis was made for
ICH and not for Langerhans cell histiocytosis (LCH).

Indeterminate cell histiocytosis is morphologically similar to
Langerhans cell histiocytosis (LCH). Previous studies have found that
there are two relationship models between LCH and
tumor\textsuperscript{{[}3{]}}. Bubolz \emph{et
al.}\textsuperscript{{[}4{]}} reported that the average of BRAFV600E
oncogene was 48.5\% in LCH. Elsewhere, Badalian-Very G \emph{et
al.}\textsuperscript{{[}5{]}} found a recurrent mutation of the
BRAFV600E gene in LCH. The BRAF V600E mutation has been detected in two
out of seven ICH cases \textsuperscript{{[}6{]}}. Generally, BRAF gene
has been verified as an oncogene in many studies, which was involved in
colorectal cancer, liver cancer, pancreatic cancer, malignant melanoma
and papillary thyroid carcinoma. It played a crucial role in the process
of tumorigenesis, development and transfer \textsuperscript{{[}7-9{]}}.
Therefore, mutation of BRAF V600E could be the reason for our case with
ICH following esophageal~cancer. Apart from BRAF V600E mutation,
ETV3-NCOA2 translocation has been found in some ICH
cases\textsuperscript{{[}10{]}}.

Bullous pemphigoid (BP) is an autoimmune blistering disorder that
primarily occurs in elderly men. However, the relationship between BP
and cancer is still controversial. Although it has been reported that
the malignancy can occur before, during and after the appearance of
typical bullous skin lesions, the detailed pathogenetic mechanism of the
correlation remains unclear \textsuperscript{{[}11{]}}. However,
different studies have convincingly revealed that there is no relativity
between BP and tumor \textsuperscript{{[}12, 13{]}}. In our case, the
patient received the radiation therapy (RT) for esophageal carcinoma. So
the occurrence of BP may be in association with RT. Tegan \emph{et
al.}\textsuperscript{{[}14{]}} summarized the literature about
RT-associated BP and proposed different theories on the possible
mechanism about the occurrence of RT-associated BP. In addition, we
found no case reported on the association of ICH with BP. But Akdogan
\emph{et al.}\textsuperscript{{[}15{]}} presented a case of
multi-lesional cutaneous ICH in a 27-year-old male patient with SLE
together with antiphospholipid antibody syndrome (APS), which were
autoimmune disorders.

In this case, the point of attention was that esophageal carcinoma, ICH
and BP were found in a single patient and to determine whether there was
any association among them. This provided important information towards
establishing the possible mechanism between cancer and the development
of ICH and BP.

\textbf{References}

{[}1{]} Zanella S, Berti E, Bonometti A, et al. Indeterminate Cell
Histiocytosis: a systematic review of the literature with a
comprehensive revision of clinical, histopathological, and molecular
features. Journal of the European Academy of Dermatology and
Venereology, 2023;00:1--17. https://doi.org/10.1111/jdv.19095.

{[}2{]} Davick JJ, Kim J, Wick MR et al. Indeterminate dendritic cell
tumor: a report of two new cases lacking the ETV3-NCOA2 translocation
and a literature review. Am. J. Dermatopathol. 2018; 40: 736--48.

{[}3{]} Ma J, Laird J H, Chau K W, et al. Langerhans cell histiocytosis
in adults is associated with a high prevalence of hematologic and solid
malignancies. Cancer Medicine, 2019, 8(1): 58-66.

{[}4{]} Bubolz AM, Weissinge SE, Stenzinger A, et al. Potential clinical
implications of BRAF mutations in histiocytic proliferations.
0ncotarget, 2014, 5(12): 4060-4070.

{[}5{]} Badalian-Very G, Vergilio JA, Degar BA, et al. Recurrent BRAF
mutations in Langerhans cell histiocytosis. Blood, 2010, 116(11):
1919-1923.

{[}6{]} Kinoshita M, Ogawa Y, Honobe A, et al. Expression of CD1
molecules and colony-stimulating factor 1 receptor in indeterminate cell
histiocytosis. The Journal of Dermatology, 2021, 48(7): 1086-1089.

{[}7{]} Penning A J, Al-lbraheemi A, Michal M, et al. Novel BRAF gene
fusions and activating point mutations in spindle cell sarcomas with
histologic overlap with infantile fibrosarcoma. Modern Pathology, 2021,
34(8): 1530-1540.

{[}8{]} Chen D, Su X, Zhu L, et al. Papillary thyroid cancer organoids
harboring BRAFV600E mutation reveal potentially beneficial effects of
BRAF inhibitor-based combination therapies. Journal of Translational
Medicine, 2023, 21(1): 1-18.

{[}9{]} Hussen B M, Azimi T, Abak A, et al. Role of lncRNA BANCR in
human cancers: an updated review. Frontiers in Cell and Developmental
Biology, 2021, 9: 689992.

{[}10{]} Belina M E, Kwock J T, Al-Rohil R, et al. An Atypical
Myelomonocytic Cell Infiltrate: Use of Next-Generation Sequencing to
Diagnose Indeterminate Cell Histiocytosis. The American Journal of
Dermatopathology, 2022, 44(7): 529-531.

{[}11{]} Asdourian M S, Shah N, Jacoby T V, et al. Association of
bullous pemphigoid with immune checkpoint inhibitor therapy in patients
with cancer: a systematic review. JAMA dermatology, 2022, 158(8):
933-941.

{[}12{]} Chen C T, Hu H Y, Chang Y T, et al. Cancer is not a risk factor
for bullous pemphigoid: 10-year population-based cohort study. British
Journal of Dermatology, 2019, 180(3): 553-558.

{[}13{]} Shen W C, Chiang H Y, Chen P S, et al. Risk of all-cause
mortality, cardiovascular disease mortality, and cancer mortality in
patients with bullous pemphigoid. JAMA dermatology, 2022, 158(2):
167-175.

{[}14{]} Tegan Nguyen, Julia M, Kwan A, et al.
Relationship~between~radiation therapy~and~bullous pemphigoid.
Dermatology,~2014, 229(2): 88-96.

{[}15{]} Akdogan N, Demircan C, Bolek E C, et al. Indeterminate cell
histiocytosis in a patient with systemic lupus erythematosus and
antiphospholipid antibody syndrome: an unusual association{[}J{]}.
Lupus, 2020, 29(1): 74-78.\selectlanguage{english}
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\textbf{Figure 1: Annular erythema over his chest(B), abdomen(B),
limbs(A, C, D), and bullous (the arrow) on the thigh.}\selectlanguage{english}
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\selectlanguage{ngerman}\textbf{Figure 2: Histology of the skin biopsy. A) the lesion of abdomen
(HE, 400×); B) the lesion of the blister of thigh (HE, 200×).}\selectlanguage{english}
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\selectlanguage{ngerman}\textbf{Figure 3. Immunohistochemical findings of the patient (200×).}

\textbf{CD1a strong positive in the epidermal and dermal;}

\textbf{B) S100 protein positive in the epidermal and dermal;}

\textbf{C) CD68 positive in the epidermal and dermal;}

\textbf{D) CD207(Langerin) negative in the dermal.}\selectlanguage{english}
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\textbf{Figure 4}

\textbf{Figure 4: A) Clinical photograph of} \textbf{bullous pemphigoid
on the lower limbs;}

\selectlanguage{ngerman}\textbf{B) Histopathologic examination showed the subepidermal blister
(HE, 200×);}

\textbf{C) Direct immunofluorescent showed that IgG deposited in the
basal membrane zone (100×).}

\textbf{TABLE 1 Timeline of the patient}

Abbreviations: ICH, indeterminate cell histiocytosis; BP, bullous
pemphigoid\selectlanguage{english}
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