Accepted Manuscript: 10.1016/j.amjmed.2018.04.015

Parwathi “Uma” Paniker, MD, Images in Dermatology Editor
Accepted Manuscript
At the Root: CUTANEOUS LANGERHANS CELL

HISTIOCYTOSIS,,✯✯✯,✯✯✯✯
Roberto Maglie MD , Margherita Vannucchi MD ,

Lavinia Quintarelli MD , Marzia Caproni MD, PhD ,
Daniela Massi MD, PhD , Emiliano Antiga MD, PhD
PII: S0002-9343(18)30392-9
DOI: 10.1016/j.amjmed.2018.04.015
Reference: AJM 14643
To appear in: The American Journal of Medicine
Received date: 26 December 2017

Revised date: 11 April 2018
Accepted date: 11 April 2018
Please cite this article as: Roberto Maglie MD , Margherita Vannucchi MD , Lavinia Quintarelli MD ,
Marzia Caproni MD, PhD , Daniela Massi MD, PhD , Emiliano Antiga MD, PhD , At the Root: CUTA-
NEOUS LANGERHANS CELL HISTIOCYTOSIS,,✯✯✯,✯✯✯✯ , The American Journal of Medicine (2018),
doi: 10.1016/j.amjmed.2018.04.015
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TITLE: At the Root: CUTANEOUS LANGERHANS CELL HISTIOCYTOSIS.
AUTHORS: Roberto Maglie, MD1, Margherita Vannucchi, MD2, Lavinia Quintarelli, MD1, Marzia
Caproni, MD, PhD1, Daniela Massi, MD, PhD2, Emiliano Antiga, MD, PhD1.
1
Dermatology Unit, Department of Surgical and Translational Medicine, University of Florence,
Florence, Italy.
2
Division of Pathological Anatomy, Department of Surgery and Translational Medicine, University
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of Florence, Florence Italy.
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Corresponding author:
Roberto Maglie, MD
Department of Medical and Surgical Critical Care, Section of Dermatology, University of Florence.
Viale Michelangelo 41,50125, Florence, Italy
Phone: +39 055 6939627
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e-mail: robertomaglie.med@libero.it.
Conflicts of interest: The authors of this manuscript declare no conflicts of interest.

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All authors had access to the data and a role in writing the manuscript.
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Funding: none
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Article type: Images in Dermatology.

Key words: Langerhans cell histiocytosis, female androgenic alopecia, seborrheic dermatitis.
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Word count (including manuscript, references and figure legend): 1501.

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Figure count: 3
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Images in Dermatology
At the Root: Cutaneous Langerhans Cell Histiocytosis
Parwathi ―Uma‖ Paniker, MD

Images in Dermatology Editor
Roberto Maglie, MD,a Margherita Vannucchi, MD,b Lavinia Quintarelli, MD,a Marzia Caproni, MD,
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PhD,a Daniela Massi, MD, PhD,b Emiliano Antiga, MD, PhDa
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a
Section of Dermatology and bDivision of Pathological Anatomy, Department of Surgery and
Translational Medicine, University of Florence School of Human Health Sciences, Florence, Italy.
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Requests for reprints should be addressed to Roberto Maglie, MD, Department of Surgery and
Translational Medicine, Section of Dermatology, University of Florence, Viale Michelangelo 41,
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50125, Florence, Italy.
Email address: robertomaglie.med@libero.it

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PRESENTATION
Hair loss is of deep concern to patients, mainly because of its effect on appearance. On rare
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occasions, though, areas of balding can signal malignancy. A 33-year-old woman was referred to
our dermatology clinic because of a 15-year history of scalp eruption accompanied by intense
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itching and progressive hair loss. Previously, she was diagnosed with seborrheic dermatitis
associated with female androgenic alopecia. She was treated with topical steroids for many years
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without improvement, except for transient relief of itching. Five years before her referral to our
clinic, she underwent surgery for an in situ melanoma of the leg. Otherwise, her past medical
history was unremarkable.
ASSESSMENT
Physical examination revealed moderate hair thinning of the frontoparietal scalp, a finding in line
with the diagnosis of female androgenic alopecia (Figure 1). Numerous follicular-based,
erythematous, scaling papules with overlying yellow to brown crusts were noted on the
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parietotemporal and vertex areas of the patient’s scalp, where hair thinning was striking. The
interfollicular skin appeared atrophic, as a result of the prolonged steroid applications, but was
without erythema or scaling. Areas of scarring alopecia were absent (Figure 2 A and B). The rest of
the examination was unremarkable. Laboratory investigations, including a complete blood count, a
full hormonal and metabolic panel, antinuclear antibody levels, and the erythrocyte sedimentation
rate, showed no abnormalities.
The diagnosis of seborrheic dermatitis was questioned because the condition manifests with
erythema and desquamation of the scalp and involves both perifollicular and interfollicular skin. At
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the same time, the patient’s hair loss in the parietotemporal and vertex regions could not be
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explained by her previous diagnosis of androgenic alopecia, which commonly spares those areas in
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females.
Thus, a 4-mm punch biopsy was taken from a papular lesion. Histopathology showed
dermoepidermal detachment and a dermal infiltrate composed of what appeared to be Langerhans
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cells, clusters and sheets of large ovoid cells with abundant eosinophilic cytoplasm and a reniform
nucleus. This accumulation of cells tended to have a periadnexal distribution, leading to follicular
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atrophy, and it was mixed with numerous lymphocytes, plasma cells, neutrophils, and eosinophils.
Immunohistochemical analysis produced reactions with antibodies against CD1a and S100
protein, confirming the presence of Langerhans cells (Figure 3, A-F). Immunohistochemical
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analysis to detect the BRAF V600E mutation in lesional tissue was negative. Molecular analysis
through mass spectrometry base sequencing (Sequenom Laboratories, San Diego, CA) confirmed
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the absence of the BRAF V600E mutation.

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DIAGNOSIS
Based on the combined clinical, histological, and molecular findings, a diagnosis of Langerhans cell
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histiocytosis was made. To stage the disease, a total-body computed tomography scan and positron
emission tomography were performed. No internal organ involvement was seen.
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Langerhans cell histiocytosis is a malignant histiocytic disorder, affecting 1-2 adults and 5-9
children per million.1 Clinical variants, ranging from self-healing to life-threatening, are
characterized by the proliferation of myeloid precursors of dendritic cells with ultrastructural and
immunophenotypic features of epidermal Langerhans cells.2 In adults, skin-limited forms are rare;
most patients with cutaneous involvement display localized disease in internal organs.3 Nowadays,
cutaneous manifestations occur in nearly 40% of patients.4
Cutaneous Langerhans cell histiocytosis preferentially localizes to cutaneous areas where
there is a high production of sebum—areas where seborrheic dermatitis typically occurs—and
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flexures. Widespread eruptions or the involvement of genitalia and mucous membranes are also
common. The clinical presentation frequently overlaps with that of benign inflammatory diseases,
including intertrigo, seborrheic dermatitis, prurigo nodularis or infections. As a result, diagnosis
may be significantly delayed, as the clinical findings generally do not suggest Langerhans cell
histiocytosis.5 Rather, Langerhans cell histiocytosis is most commonly suspected when cutaneous
lesions fail to improve with local treatments.
Our patient experienced an unusual presentation. Although there have been reports of
Langerhans cell histiocytosis confined to the scalp, including cases with folliculocentric infiltrates,
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all patients retained normal hair growth.6 Her diagnosis of androgenic alopecia, which frequently
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coexists with severe seborrheic dermatitis, represented a major diagnostic pitfall, as it obscured the
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true cause of hair loss in zones other than the frontoparietal area. In those regions, Langerhans cell
histiocytosis infiltrated the hair follicles.
Regardless of the organ involved, the diagnosis of Langerhans cell histiocytosis needs to be
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confirmed by histopathological and immunohistochemical analyses and eventually, by detecting
Birbeck granules through electronic microscopy.7 In our patient’s case, pathologic histiocytes were
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positive for the Langerhans cell antigens CD1a and S100 protein, allowing us to exclude other
histiocytic or macrophage-dendritic cell neoplasms.
Over 50% of patients with Langerhans cell histiocytosis harbor the BRAF V600E hotspot
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mutation. Additional mutations have been found in other mitogen-activated protein (MAP)-kinase
genes, highlighting the pivotal role of that type of oncogenic signaling in a subset of patients. The
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clinical heterogeneity of Langerhans cell histiocytosis is likely to depend on several elements,

including the patient’s specific MAP-kinase gene mutation and the manner in which that gene
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influences the differentiation of the dendritic cell precursor.8

Neither immunohistochemistry nor molecular analysis identified the BRAF V600E mutation
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in our patient. It is possible to speculate that a yet-unknown clonal event occurred in a mature
Langerhans cell precursor committed to the scalp skin and hair follicles, explaining the absence of
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systemic disease or additional cutaneous localizations and the indolent clinical course of the
patient’s illness.
MANAGEMENT
Treatment of Langerhans cell histiocytosis has to be based on the extent of the patient’s disease and
the expected outcome. Adult patients with multisystem disease are candidates for chemotherapy,
usually vinblastine-containing regimens. For those harboring the BRAF V600E mutation, the
BRAF kinase inhibitor vemurafenib has shown excellent results, but relapse is invariably observed
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upon treatment discontinuation. Even with treatment, adult Langerhans cell histiocytosis is
associated with long-term morbidity and an overall mortality rate of 3%.9
Patients with skin-limited disease may benefit from less aggressive approaches. Treatment
with oral methotrexate, 6-mercaptopurine, topical corticosteroids, topical nitrogen mustard
(mechlorethamine), or oral thalidomide have reportedly been effective.4
Although Langerhans cell histiocytosis limited to the skin generally has a better outcome
than multisystemic forms, patients with cutaneous disease may develop systemic involvement, and
they have a higher risk of secondary hematologic malignancies, mostly Hodgkin’s lymphoma.10
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Therefore, multidisciplinary follow-up by general practitioners, hematologists, radiologists, and
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dermatologists, is important. While no formal recommendations exist, laboratory testing, including
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a complete blood count, a full hormonal and metabolic panel, lactate dehydrogenase and beta-2
microglobulin levels, ultrasonography of the abdomen, and a chest x-ray could be recommended
every 6 months.
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Our patient was prescribed oral methotrexate, and treatment is currently ongoing. She has
had moderate improvement of her symptoms. Her Langerhans cell histiocytosis, initially
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misdiagnosed as seborrheic dermatitis, was associated with progressive alopecia. Fortunately, no
life-threatening complications occurred despite the extended delay in a correct diagnosis. Her
disease remains confined to the skin. Clinicians should remember to include Langerhans cell
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histiocytosis in the differential diagnosis when a patient has inflammation-like skin eruptions that
are unexpectedly resistant to classic treatments.
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References
1. Stålemark H, Laurencikas E, Karis J, Gavhed D, Fadeel B, Henter JI. Incidence of
Langerhans cell histiocytosis in children: A population-based study. Pediatr Blood Cancer.
2008;51:76–81.
2. Egeler RM, van Halteren AGS, Hogendoorn PCW, Laman JD and Leenen PJM. Langerhans
cell histiocytosis: fascinating dynamics of the dendritic cell–macrophage lineage. Immunol
Rev. 2010;234:213–232.
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3. Zhang S, Liu Y. Langerhans cell histiocytosis in an adult female presenting with widespread
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confluent crusted papules and review of adult cases confined to skin. Int J Dermatol.
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2017;56:1182-1185.
4. Roider E, Signer C, Fehrenbacher B, et al. Individualized treatment approaches for
Langerhans Cell Histiocytosis. Br J Dermatol. 2017 Nov 30. doi:10.1111/bjd.16171.
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5. Girschikofsky M, Arico M, Castillo D, et al. Management of adult patients with Langerhans
cell histiocytosis: recommendations from an expert panel on behalf of Euro-Histio-Net.
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Orphanet J Rare Dis. 2013;8:72.
6. Hancox JG, James AP, Madden C, Wallace CA, McMichael AJ. Adult onset folliculocentric
Langerhans cell histiocytosis confined to the scalp. Am J Dermatopathol. 2004;26:123-126.
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7. Nguyen E, Claar D, McGuinn E, Mast K, Hartley K, McDonagh K. Persistence pays off:

adult Langerhans cell histiocytosis. Am J Med. 2016;129:e55-59. doi:
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10.1016/j.amjmed.2016.02.018.
8. Allen CE, Ladisch S, McClain KL. How I treat Langerhans cell histiocytosis. Blood.
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2015;126:26-35.
9. Bernstrand C, Sandstedt B, Ahström L, Henter JI. Long-term follow-up of Langerhans cell
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histiocytosis: 39 years' experience at a single centre. Acta Paediatr. 2005;94:1073-1084.

10. Edelbroek JR, Vermeer MH, Jansen PM, et al. Langerhans cell histiocytosis first presenting
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in the skin in adults: frequent association with a second haematological malignancy. Br J

Dermatol. 2012;167:1287-1294.
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FIGURE LEGENDS
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Figure 1 Thinning of the hair in the frontoparietal scalp was due to androgenic alopecia.
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Figure 2. A, Loss of hair in the parietotemporal and vertex areas of the scalp was associated with
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perifollicular brown-yellow scales and crusts. B, This image offers a closer look at the scalp lesions.
The patient’s interfollicular skin appeared normal.
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Figure 3 A, A histologic sample revealed a dense accumulation of Langerhans cells in the

superficial and deep dermis. The Langerhans cells showed epidermotropism—they localized in the
epidermis—and this caused dermoepidermal detachment and intraepidermal abscess (hematoxylin
and eosin, 5x). B, At higher magnification, a proliferation of large ovoid cells with folded, lobulated,
or reniform nuclei and abundant eosinophilic cytoplasm could be seen in the dermal infiltrate
(hematoxylin and eosin, 40x). C, The proliferation of Langerhans cells was accompanied by an
infiltrate consisting of lymphocytes, plasma cells, neutrophils, and eosinophilic granulocytes
(hematoxylin and eosin, 20x). D, Langerhans cells surrounded and penetrated the hair follicle and
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the adnexa (hematoxylin and eosin, 20x). E, The Langerhans cells were positive for CD1a (CD1a
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immunostain, 20x). F, They were also positive for S-100 protein (S-100 immunostain, 20x).
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Parwathi “Uma” Paniker, MD, Images in Dermatology Editor

At the Root: CUTANEOUS LANGERHANS CELL

Roberto Maglie MD , Margherita Vannucchi MD ,

To appear in: The American Journal of Medicine

Received date: 26 December 2017

TITLE: At the Root: CUTANEOUS LANGERHANS CELL HISTIOCYTOSIS.

Conflicts of interest: The authors of this manuscript declare no conflicts of interest.

Article type: Images in Dermatology.

Word count (including manuscript, references and figure legend): 1501.

At the Root: Cutaneous Langerhans Cell Histiocytosis

Parwathi ―Uma‖ Paniker, MD

Email address: robertomaglie.med@libero.it

the absence of the BRAF V600E mutation.

clinical heterogeneity of Langerhans cell histiocytosis is likely to depend on several elements,

influences the differentiation of the dendritic cell precursor.8

7. Nguyen E, Claar D, McGuinn E, Mast K, Hartley K, McDonagh K. Persistence pays off:

histiocytosis: 39 years' experience at a single centre. Acta Paediatr. 2005;94:1073-1084.

in the skin in adults: frequent association with a second haematological malignancy. Br J

Figure 3 A, A histologic sample revealed a dense accumulation of Langerhans cells in the

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