Immunohistochemical Analysis of Prurigo Nodularis in 209 Patients: Clinicopathological Analysis between Atopic and Non-Atopic Patients and between ...
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Clinicopathological Analysis of Prurigo Nodularis
pISSN 1013-9087ㆍeISSN 2005-3894
Ann Dermatol Vol. 33, No. 4, 2021 https://doi.org/10.5021/ad.2021.33.4.333
ORIGINAL ARTICLE
Immunohistochemical Analysis of Prurigo Nodularis in
209 Patients: Clinicopathological Analysis between
Atopic and Non-Atopic Patients and between Treatment
Response Groups
Hyun Jeong Byun, Donghwi Jang, Dong-Youn Lee, Jun-Mo Yang
Department of Dermatology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
Background: Prurigo nodularis (PN) is a highly pruritic dis- proved groups. Conclusion: Implementing the special stains
ease that significantly impairs patient quality of life. Although helped to identify PN pathogenesis. Because there were no
the mechanism that causes pruritus is not clear, one hypoth- statistically significant differences in the special stain results
esis argues that neural hyperplasia, mast cell, and Merkel cell between the improved and non-improved groups, we con-
neurite complexes may be associated with PN pathogenesis. clude that mast cell proliferation, neural hyperplasia, and
Objective: The objective of this study was to analyze wheth- Merkel cell hyperplasia may not have a significant effect on
er special staining outcomes differed depending on the pres- treatment response. (Ann Dermatol 33(4) 333∼338, 2021)
ence of atopic dermatitis (AD) and treatment response.
Methods: A total of 209 patients diagnosed with PN was ana- -Keywords-
lyzed retrospectively. Patients were divided into two groups Atopic dermatitis, Mast cells, Merkel cells, Nerve fibers,
according to presence or past history of AD and by treatment Prurigo
response. Histopathologic features were obtained using the
following stains: Giemsa, S-100, neuron-specific enolase,
cytokeratin (CK)-20, CAM5.2, and CK8/CK18. Results: A to- INTRODUCTION
tal of 126 patients (60.29%) had AD, and 68 (32.54%)
showed clinical improvement. There were no statistically Prurigo nodularis (PN) is a highly pruritic, hyperkeratotic
significant differences in the staining results between the PN papule and nodular disease. PN is common in the 50 to
groups with AD (PN c̅ AD) and without AD (PN s̅ AD). 60 years age group; however, it can also develop in
Additionally, there were no statistically significant differ- younger people in association with atopic dermatitis
1,2
ences in staining results between the improved and non-im- (AD) . PN significantly impairs quality of life, which can
3,4
cause psychological distress and sleep disturbance .
Received August 20, 2020, Revised November 25, 2020, Accepted for Repeated scratching of the lesions leads to excoriation and
publication November 26, 2020 lichenification, mainly on the extensor surfaces, trunk, or
Corresponding author: Jun-Mo Yang, Department of Dermatology, Samsung lower extremities1,5. PN is associated with a wide range of
Medical Center, Sungkyunkwan University School of Medicine, 81 diseases including AD, various infectious diseases, chronic
Irwon-ro, Gangnam-gu, Seoul 06351, Korea. Tel: 82-2-3410-3541, Fax:
82-2-3410-3869, E-mail: junmo.yang@samsung.com kidney disease, malignancies, and neurological dis-
ORCID: https://orcid.org/0000-0003-0656-8046 eases6-11. Thus, PN is sometimes considered to be a clin-
This is an Open Access article distributed under the terms of the Creative ical pattern induced by chronic pruritus and repeated
Commons Attribution Non-Commercial License (http://creativecommons. 5
scratching and common histopathologic presentations in-
org/licenses/by-nc/4.0) which permits unrestricted non-commercial use,
distribution, and reproduction in any medium, provided the original work clude orthohyperkeratosis, acanthosis, parakeratosis, pap-
is properly cited. illary dermal fibrosis with perivascular inflammatory in-
12,13
Copyright © The Korean Dermatological Association and The Korean filtrations, and characteristic neural hypertrophy . Several
Society for Investigative Dermatology
previous studies have reported changes in nerve, Merkel,
Vol. 33, No. 4, 2021 333HJ Byun, et al
12,14,15
and mast cells . Although the mechanism of pruritus tihistamine prescriptions were adjusted as needed. Signs
is not clear, one hypothesis suggests that neural hyper- of improvement included diminished itching or relieved
plasia, mast cell, and Merkel cell neurite complexes may cutaneous lesions such that the antihistamine treatment
be associated with PN pathogenesis1,15-20. The objective of frequency could be reduced or stopped. Patients with
this study was to analyze whether special staining out- minimal clinical symptom change in their skin lesions or
comes differed according to clinical features such as pres- who required additional antihistamines during a follow-up
ence of AD and treatment response. appointment were considered to have no improvement in
their condition. Treatment with topical 0.1% methyl-
MATERIALS AND METHODS prednisolone and topical 0.1% tacrolimus ointment was
maintained for all patients for six months. Patients were
This was a retrospective study using electronic medical divided into two groups according to presence or past his-
records. The ethical committees of Samsung Medical Center tory of AD and according to treatment response. Histo-
approved this study (approval number: 2002-10-009, pathologic features were obtained from hematoxylin and
2009-12-053). Subjects included were patients who vis- eosin (H&E) stained slides and from the other six special
ited the Department of Dermatology at Samsung Medical stains. The chi-square test, Fisher’s exact test, and logistic
Center from May 2012 to May 2016 and underwent skin regressions were used, and all statistical analyses were
punch biopsy with special staining under clinical diag- performed using SAS version 9.4 (SAS Institute, Cary, NC,
nosis of PN. A total of 243 patients were clinically sus- USA).
pected of PN, and underwent skin punch biopsy and as-
sessment through several special stains: Giemsa, S-100, RESULTS
neuron-specific enolase (NSE), cytokeratin (CK)-20, CAM5.2,
and CK8/CK18. We excluded 34 patients who were diag- A total of 209 patients were included in the analyses.
nosed with diseases other than PN such as capillary he- Males accounted for 52.63% of the study sample. The
mangioma, bullous pemphigoid, or lichen simplex chron- average age of onset for all patients was 52.96 years. The
icus; thus, 209 patients were analyzed (Fig. 1). average age of onset was 50.19 years for female patients
When patients visited the clinic, the physician first took and 55.45 years for male patients, which is significantly
their medical history including AD history. Next, skin bi- different (p=0.017). The majority of patients (126/209;
opsy was performed with special stains. On the same day, 60.29%) had AD or a history of AD. The average AD pa-
oral antihistamines with topical 0.1% methylprednisolone tient age was 52.78 years, and the average age of patients
and topical 0.1% tacrolimus were prescribed. Two weeks without AD was 53.24 years; this difference was not stat-
later, the physician checked the skin biopsy results and istically significant (p=0.838). Among the 209 patients di-
adjusted the antihistamines as needed. Patients were fol- agnosed with PN after skin biopsy, 75 were lost to fol-
lowed-up every two to four weeks for six months, and an- low-up within 3 months. While 68 patients experienced
Fig. 1. Patient flowchart. PN:
prurigo nodularis.
334 Ann DermatolClinicopathological Analysis of Prurigo Nodularis
clinical improvement, 66 patients showed no improve- tients including patients who lost follow up, and 134 pa-
ment within 6 months (Fig. 1). Clinical improvement was tients without them, we found no statistically significant
observed in 68 patients (32.54%) (Table 1), but the im- differences between the improved and non-improved
provement status of the 75 patients who were lost to fol- groups (Table 3).
low-up is unknown. Thus, when analyzing the 134 pa-
tients with more than 3 months of follow-up data, 50.75% DISCUSSION
showed clinical improvement.
Skin punch biopsy with six special stains was conducted. PN is known to be induced by pricking and scratching,
Giemsa staining was performed to identify mast cell pro- secondary to itching13. A number of pathways have been
liferation, and S-100 and NSE were used to identify neural suggested to explain heightened perception to itch and
hyperplasia. CK-20, CAM5.2, CK8/CK18 stains were used touch in PN patients13. These include neurochemical
to observe Merkel cell hyperplasia. With Giemsa staining, changes in cutaneous nerves in the lesions, the spinal
mast cell proliferation was seen in 8.1% of patients (Table cord, and the central nervous system13. PN lesions show
2). S-100 stain was positive for nerve proliferation in nerve hyperplasia and elevated numbers of cutaneous
15.3% of patients and NSE was positive in 27.3% of pa- nerve fibers, as indicated by positive staining for neuro-
tients, with neural hyperplasia being observed in 32.1% peptides such as substance P and calcitonin gene-related
(n=67; Table 2). CK-20, CAM5.2, and CK8/CK18 were peptide (CGRP)1. A previous report indicated that in-
positive in 0.96%, 17.7%, and 43.1% of patients, respec- creased CGRP and substance P-immunoreactive nerve fi-
tively, and Merkel cell hyperplasia was observed in 61.2% bers is a characteristic feature of PN1. Nerve growth factor,
21
(n=128; Table 2). which is released from mast cells , is overexpressed in
The relationship between special staining outcomes and PN lesions and may induce hypersecretion of neuro-
AD history was analyzed. Giemsa stain yielded a statisti- peptides, such as substance P and calcitonin CGRP, from
cally significant difference between the PN groups with sensory fibers, resulting in neuropeptide deposition in pru-
AD (PN c̅ AD) and PN groups without AD (PN s̅ AD) ritic nodules15,17,22. Neuropeptides promote mast cell de-
(p=0.0280; Table 3). In logistic regression models, Giemsa granulation and release of mediators like histamines,
stain was expressed significantly less in PN c̅ AD patients which not only induces itching in the skin, but also in-
than PN s̅ AD patients (odds ratio=0.0347). The relation- creases fibroblast proliferation and collagen synthesis that
ship between special staining outcomes and treatment re- causes collagen remodeling20,23. Increased Merkel cell
sponse were also analyzed. When analyzing both 209 pa- density has also been reported to be associated with neu-
ronal proliferation in PN lesions because they are compo-
Table 1. Clinical characteristics of patients with prurigo nodularis
(total=209) Table 2. Special staining results for patients with prurigo
nodularis
Clinical feature Value
No. of No. of
Mean age of onset (yr)
specimens with specimens with
Total 52.96 (15.93) Special stain
positive stains positive stains
Male 55.45 (14.60)
(n=209) (n=134)
Female 50.19 (17.00)
Sex Mast cell proliferation
Male 110 (52.63) Giemsa 17 (8.1) 13 (9.7)
Female 99 (47.37) Total 17 (8.1) 13 (9.7)
Male:female 1.1:1 Neural hyperplasia
Atopic dermatitis S-100 32 (15.3) 19 (14.2)
Atopic 126 (60.29) NSE 57 (27.3) 35 (26.1)
Non-atopic 83 (39.71) Total 67 (32.1) 41 (30.6)
Treatment response Merkel cell hyperplasia
Improvement 68 (32.54)* CK-20 2 (1.0) 2 (1.5)
No improvement 66 (31.58) CAM5.2 37 (17.7) 24 (17.9)
Follow-up loss 75 (35.89) CK8 and CK18 90 (43.1) 58 (43.3)
Total 128 (61.2) 83 (61.9)
Values are presented as mean (standard deviation) or number (%).
*When 75 patients who were lost to follow-up were excluded, Values are presented as number (%). NSE: neuron-specific
50.75% clinically improved. enolase, CK: cytokeratin.
Vol. 33, No. 4, 2021 335HJ Byun, et al
nents of the neurocutaneous system response to light
p-value
0.4962
0.3962
0.8323
touch18. The authors recognized that PN pathophysiology
is closely related to nerve, Merkel, and mast cells. Skin bi-
opsies were performed from patients with clinically sus-
63 (70.0)
31 (53.4)
35 (38.9)
27 (30.0)
27 (46.6)
55 (61.1)
CK8 and
positive
CK18
pected PN, including special stains for the three cell types
90
58
90
above, to determine if they were actually associated with
PN.
Merkel cell hyperplasia
p-value
Our study results were reviewed in context with the pre-
0.7099
0.7114
0.9097
vious literature. CK-20, CAM5.2, and CK8/CK18 staining
were performed to evaluate Merkel cell hyperplasia, which
CAM 5.2
24 (64.9)
11 (45.8)
13 (35.1)
13 (54.2)
15 (40.5)
22 (59.5)
positive
is a characteristic feature of PN. In a previous study, 75%
37
24
37
of tissues tested positive in CK8 staining, indicating ele-
Values are presented as number only or number (%). NSE: neuron-Specific Enolase, CK: cytokeratin. *Statistically significant (pClinicopathological Analysis of Prurigo Nodularis
special staining outcomes and clinical features of PN. non-atopic diseases: aetiological survey in a consecutive
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