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Observation Letter
ARTICLE IN PRESS
doi:
10.25259/IJDVL_50_2021

Nail involvement in Langerhans cell histiocytosis and its association with multisystem presentation and lung involvement

Department of Molecular Medicine, Unit of Anatomic Pathology, IRCCS San Matteo Foundation, University of Pavia, Pavia, Italy
Department of Dermatology, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy
Department of Oncology, Medical Oncology 1, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
Corresponding author: Dr. Arturo Bonometti, Department of Molecular Medicine, Unit of Anatomic Pathology, IRCCS San Matteo Foundation, University of Pavia, Pavia, Italy. arturo.bonometti11@gmail.com
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This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-Share Alike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.

How to cite this article: Bonometti A, Passoni E, Finotto S, Berti E. Nail involvement in Langerhans cell histiocytosis and its association with multisystem presentation and lung involvement: Case study and a comprehensive review of the literature. Indian J Dermatol Venereol Leprol, doi: 10.25259/IJDVL_50_2021

Sir,

Langerhans cell histiocytosis is a rare proliferation of cells of the mononuclear-phagocyte system mainly affecting children.1

The great heterogeneity of clinical presentation requires histopathological confirmation and a multidisciplinary approach. According to the number of involved sites, Langerhans cell histiocytosis is clinically classified into single-system or multisystem, the latter having a poor prognosis especially when “risk-organs” are involved.1

Nail involvement with varying morphology of changes has been reported, though rarely, in Langerhans cell histiocytosis. Nail involvement has also been considered an unfavorable prognostic sign and seems to be more frequent in multisystemLangerhans cell histiocytosis.2-4

A 41-year-old previously healthy Caucasian man, presented in October 2019, with multiple cutaneous erythematous papules over the scalp, persistent chronic paronychia with onychodystrophy and nail discoloration involving only the fifth finger of the right hand [Figure 1]. Differential diagnoses included onychomycosis, chronic candidiasis, Darier disease and Langerhans cell histiocytosis.

Figure 1a:: The patient displayed an involvement of the fifth finger, featuring chronic paronychia with onychodystrophy and a discoloration of the nail lamina.
Figure 1b:: The skin biopsy of a papular lesion of the scalp revealed a marked dermal, epidermotropic infiltrate made of medium-sized mononuclear cells admixed with macrophages, eosinophils and lymphocytes (H & E, ×20)
Figure 1c:: A marked dermal, epidermotropic infiltrate made of medium-sized mononuclear cells with large indented nuclei admixed with macrophages, eosinophils and lymphocytes. (H & E, ×200)

A diagnostic biopsy of both skin and nail was performed. Both the biopsies revealed findings consistent with Langerhans cell histiocytosis. Complete skeletal survey, whole body computed tomography, laboratory, pulmonary and hematological investigations were normal ruling out the involvement of other organs hence depicting a single-system-Langerhans cell histiocytosis. Sequenced BRAF gene revealed wild-type and it was decided to follow up the patient with only symptomatic treatment. The clinical picture is stable even fourteen months into follow up.

We queried the PubMed database, searching for all the combinations of the word “nail” and synonyms of Langerhans cell histiocytosis. Deduplication, exclusion of non-relevant records and reference list analysis yielded 34 papers, describing a total of 38 patients.

The medical literature currently reports only 38 cases of Langerhans cell histiocytosis with associated nail involvement [Tables 1 and 2]. Most reported patients were young boys. In all but two cases, patients presented with cutaneous, nail and often systemic involvement.

Table 1:: Epidemiological and clinical data of 39 LCH patients with nails involvement gathered from the literature, including the present report of year of publication
# Author Year Age/sex/ethnicity Clinical presentation Skin/mucosae n. nails involved Nail biopsy Bone Lung RO+ CNS Outcome Follow-up (mo)
Author TEs
1 Bender B 1958 43/F/Cauca MS RO+ x >1 x x x PD 48
2 Kahn 1969 3/F/Caucasi MS RO+ x 10 x x PR 18
3 Civatte 1977 40/M/Cauc MS RO+ x >1 x x x DOD 108
4 Diestelmeier 1982 2/M MS RO- x >1 x x CR 4
5 Harper 1983 1/M MS RO- x >1 x x DOD 5
6 Timpatanapong (4) 1984 2/M/Asian MS RO+ x 10 x x DOD 30
7 Timpatanapong (6) 1984 1/M/Asian MS RO+ x 20 x x x DOD 10
8 Timpatanapong (7) 1984 2/M/Asian MS RO+ x 20 x x x DOD 12
9 Ellis 1985 12/M SS x 1 CR 21
10 Holzberg 1985 0/M MS RO+ x >1 x x DOD 19
11 Pareek 1985 20/M/Causi MS RO- x 10 x DOD 48
12 Munro 1988 45/M MS RO- x >1 x x SD 4
13 Satriano (1) 1988 30/M MS RO- x >1 x x
14 Satriano (2) 1988 35/F MS RO- x >1 x
15 Alsina 1991 31/M MS RO- x 2 x x x PR 5
16 De Berker 1994 0/M/Caucas MS RO- x >1 x SD 4
17 Jain 2000 30/M/Cauc MS RO- x >1 x 2
18 Mendes 2006 3/M MS RO- x 10 x x CR 24
19 Moravvej 2006 20/M/Cauc SS x 20 SD 6
20 Querings 2006 1/F MS RO- x 10 x SD 120
21 Ashena 2007 0/F MS RO- x 20 x x DOD 22
22 Mataix 2008 2/F MS RO- x >10 x x PR 3
23 Chander 2008 1/M MS RO+ x 20 x x DOD 4
24 Yazc 2008 3/M MS RO- x >1 x x SD 130
25 Sabui 2009 3/F MS RO+ 20 x
26 Ottink 2013 2/M MS RO- >1 x SD
27 De Jesus Semblano Bittencourt 2016 2/M MS RO+ x >10 x x LFU 1
28 Figueras-Nart 2016 10/M MS RO- x >1 x x CR 17
29 Hocazade 2016 24/F MS RO+ x 10 x x LFU 108
30 Calderòn-Castrat 2017 36/F/Cauca MS RO- x 10 x x SD 180
31 Ishikawa 2017 43/F MS RO- x 7 x
32 Kumar 2017 1/M MS RO+ x 20 x x x
33 Mahajan (1) 2017 22/M MS RO+ x 20 x x CR 11
34 Mahajan (2) 2017 43/M MS RO- x 20 x 60
35 Fu 2018 19/M MS RO+ x >1 x x
36 Bender NR 2018 10/M/Afrod SS x 20 x PD 36
37 Narayanasamy 2019 1/F MS RO+ x 20 x x PR
38 Prayogo 2019 0/M MS RO- x 20 x x DOD 3
39 Present case 2020 41/M/Cauc SS x 1 x SD 10
Table 2:: Epidemiological and clinical analysis on Langerhans cell histiocytosis patients with nails involvement gathered from the literature, including the present report
All pts. Pediatric pts. Adult pts.
n. of patients 39/39 (100) 23/39 (61.5) 16/39 (41)
M/Tot (%) 28/39 (71.8) 17/23 (73.9) 11/16 (68.8)
Median age at presentation (y) (range) 3 (0–45) 2 (0–12) 33 (19–45)
Clinical picture
Single-system n(%) 4/39 (10.3) 2/23 (8.7) 2/16 (12.5)
MS Tot n(%) 35/39 (89.7) 22/23 (95.7) 14/16 (87.5)
MS RO+ (%) 15/39 (38.5) 10/23 (43.5) 5/16 (31.3)
Skin involvement n(%) 37/39 (94.9) 22/23 (95.7) 16/16 (100)
Bone involvement n(%) 14/39 (35.9) 11/23 (47.8) 3/16 (18.8)
Lung involvement n(%) 19/39 (48.7) 13/23 (56.5) 6/16 (37.5)
CNS-ND n(%) 3/39 (7.7) 1/23 (4.3) 2/16 (12.5)
CNS-DI n(%) 12/39 (30.8) 1/24 (4.3) 11/16 (68.8)
Outcome Tot n=31 (Pediatric=21, Adults=10)
CR 5/31 (16.1) 4/21 (19) 1/10 (10)
PR 4/31 (12.9) 3/21 (14.3) 1/10 (10)
SD 8/31 (25.8) 4/21 (19) 4/10 (40)
PD 2/31 (6.5) 1/21 (4.8) 1/10 (10)
DOD 10/31 (32.3) 8/21 (8.1) 2/10 (20)
Median time to death for DOD (mo) (range) 15.5 (3–108) 11 (3–30) 78 (48–108)
Median FU (mo) (range) 18 (1–180) 18 (1–130) 29.5 (4–180)

CNS-DI: Diabetes insipidus, CNS-ND: Neurodegeneration, CR: Complete remission, DOC: Dead for other cause, DOD: Dead of disease, FU: Follow-up, LFU: Lost at follow-up, M: Male, mo: Months, MS: Multisystem, PD: Progressive disease, PR: Partial remission, pts.: Patients, Rel: Relapse, RO: Risk-organs involvement, SD: Stable disease, SS: Single-system, Tot: Total, y: Years

Nail changes included onycholysis (28/38, 73.7%), subungual hyperkeratosis (23/38, 60.5%), purpuric striae (21/38 55.3%), nail dystrophy (21/38, 55.3%), paronychia (11/38, 28.9%), pachyonychia (8/38, 21.0%) and longitudinal grooving (8/38, 21.0%). In most cases, more than one nail presented with changes and in 21/38 (55.3%) of them, all fingernails were involved. Nail involvement by Langerhans cell histiocytosis was histopathologically proven in nine cases [Table 1]. In 35 (92.3%) of cases, the nail changes were present at disease onset.

Most patients displayed multisystem Langerhans cell histiocytosis, especially in the pediatric sub-cohort (22/28, 92.8% vs. 14/16 87.5% among adult patients). Around half of the cases displayed lung involvement. Bone involvement, diabetes insipidus and risk organ involvement were seen in a third of cases each. Risk organ involvement had similar incidence in children and adults.

Two papers investigated the BRAF mutational status (including present case) and both were wild-type.4

Most patients were treated with polychemotherapy including prednisone, vinca alkaloids, 6-mercaptopurine, methotrexate, cyclophosphamide, etoposide, and/or cytosine arabinoside. 5/31 (16.1%) patients with follow-up data, achieved complete remission, while 9/31 (29.0%) died of disease after a median of 15.5 months.

Among the patients who died of the disease, most were males (7/8, 87.5%) with all fingernails involved, had a median age at diagnosis of two years (range 0–40) and all displayed multisystem involvement.

According to our review of literature, nail involvement in Langerhans cell histiocytosis is rare; it occurs more frequently in male children and is often associated with skin lesions.

Clinically, the major differential diagnosis of nail changes in Langerhans cell histiocytosis includes onychomycosis, psoriasis, chronic mucocutaneous candidiasis, Darier disease, pachyonychia and dyskeratosis congenita. Clinical, histopathological and laboratory findings are needed to confirm the diagnosis.

Nail involvement in Langerhans cell histiocytosis associates with a multisystem presentation and with an unusually high incidence of lung involvement in children. While pulmonary involvement is observed in around 25% of children with Langerhans cell histiocytosis, in our review, lung involvement occurred in 13/23, (56.5%) of pediatric patients with Langerhans cell histiocytosis with nail changes. The opposite was observed for adults, with 6/16 (37.5%) having lung involvement in patients with nail involvement, compared with 62% in the general adult Langerhans cell histiocytosis population, respectively.

Interestingly, both patients showing the involvement of a single nail (including ours), presented with single-system cutaneous involvement and displayed a favorable outcome, while most patients who had a fatal outcome showed involvement of all fingernails.

Despite BRAF mutation in Langerhans cell histiocytosis is associated with a worse prognosis in both low and high-risk patients; data are lacking concerning Langerhans cell histiocytosis patients with nail involvement. Therefore, we could not analyze this aspect in our work.5

Our review highlights an association between nail involvement in Langerhans cell histiocytosis and multisystem presentation with lung involvement in pediatric patients. This is of special interest given the rarity of the lungs involvement in Langerhans cell histiocytosis children and may be a useful and inexpensive dermatological marker of disease extent and perhaps of prognosis.

Acknowledgments

The authors would like to thank Dr. Chiara Moltrasio and Dr. Carlo Alberto Maronese for their help in the gathering of data for the preparation of the paper.

Authors’ contributions

Study concept, design and supervision: AB. AB wrote the first draft. Acquisition, analysis and interpretation of data: AB, EB. EP, SF and EB provided the data and performed clinicopathological correlations. Histological and immunohistochemical reviews were performed by AB and EB. All authors edited and approved the final draft.

Ethics approval

The study was conducted following local ethical guidelines (Fondazione IRCCS Ca' Granda Institutional review board approval #179/13).

Consent to participate and for publication

The patient’s informed consent was gathered and the study was conducted following the Helsinki declaration.

Availability of data and material

All presented data are available and accessible from international literature.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

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