10.5826/dpc.1303a182
Introduction: Few studies have evaluated the histopathological characteristics of clinical rosacea subtypes in detail.
Objectives: To assess rosacea histopathological features in correspondence to clinical subgroups.
Methods: The histopathological findings of 204 rosacea patients were analyzed retrospectively and were compared among clinical subtypes.
Results: Thirt-two percent of patients were male and 68% were female. Seventy-three patients had erythematotelangiectatic rosacea (ETR) and 110 had papulopustular rosacea (PPR), 12 were ETR + PPR, 4 ocular, 2 phymatous, and 3 had Morbihan’s edema. Perivascular and perifollicular lymphohistiocytic infiltration, perifollicular exocytosis, follicular spongiosis, and ectatic vessels were almost found in all subtypes. Solar elastosis was higher in ETR. Spongiosis, exocytosis of inflammatory cells into epidermis, acanthosis, and granulomatous reaction were higher in PPR. Inflammatory cells exocytosis was more in PPR and phymatous.  Demodex folliculorum was identified in 27% of ETR, 33.6% of PPR, 50% of phymatous, one ocular patient, and none of Morbihan edema. Demodex brevis were found in 5% of ETR, 3% of PPR, and 50% of phymatous. Demodex brevis not folliculorum was more in phymatous. Spongiosis was the most common finding in ocular rosacea. 
Conclusions: Spongiosis, exocytosis of inflammatory cells, and granulomatous reactions were more in PPR. Solar elastosis was more in ETR. Histopathological findings were compatible with clinical subgroups.
text/xml
2160-9381
2995
en
Ifa Etesami
https://creativecommons.org/licenses/by-nc/4.0
Dermatology Practical & Conceptual
subgroup
A Clinicopathological Survey of 204 Rosacea Patients Regarding Rosacea Subgroups and Severity
Text.Serial.Journal
https://dpcj.org/index.php/dpc
Original Article
2023-07-31
2022-11-18
2023-07-31
2023-08-24
e2023182
Dermatol Pract Concept
Introduction: Few studies have evaluated the histopathological characteristics of clinical rosacea subtypes in detail.
Objectives: To assess rosacea histopathological features in correspondence to clinical subgroups.
Methods: The histopathological findings of 204 rosacea patients were analyzed retrospectively and were compared among clinical subtypes.
Results: Thirt-two percent of patients were male and 68% were female. Seventy-three patients had erythematotelangiectatic rosacea (ETR) and 110 had papulopustular rosacea (PPR), 12 were ETR + PPR, 4 ocular, 2 phymatous, and 3 had Morbihan’s edema. Perivascular and perifollicular lymphohistiocytic infiltration, perifollicular exocytosis, follicular spongiosis, and ectatic vessels were almost found in all subtypes. Solar elastosis was higher in ETR. Spongiosis, exocytosis of inflammatory cells into epidermis, acanthosis, and granulomatous reaction were higher in PPR. Inflammatory cells exocytosis was more in PPR and phymatous.  Demodex folliculorum was identified in 27% of ETR, 33.6% of PPR, 50% of phymatous, one ocular patient, and none of Morbihan edema. Demodex brevis were found in 5% of ETR, 3% of PPR, and 50% of phymatous. Demodex brevis not folliculorum was more in phymatous. Spongiosis was the most common finding in ocular rosacea. 
Conclusions: Spongiosis, exocytosis of inflammatory cells, and granulomatous reactions were more in PPR. Solar elastosis was more in ETR. Histopathological findings were compatible with clinical subgroups.
Ifa Etesami
2023/07/31
10.5826/dpc.1303a182
e2023182
Department of Dermatology, Razi Hospital, Tehran University of Medical Sciences; Autoimmune Bullous Diseases Research Center, Tehran University of Medical Sciences, Tehran, Iran
2160-9381
subgroup
en
e2023182
Marson JW, Baldwin HE. Rosacea: a wholistic review and update from pathogenesis to diagnosis and therapy. Int J Dermatol. 2020;59(6):e175-e182. DOI: 10.1111/ijd.14757. PMID: 31880327.
A Clinicopathological Survey of 204 Rosacea Patients Regarding Rosacea Subgroups and Severity
https://dpcj.org/index.php/dpc/article/download/2995/2203
Clinicopathological Survey of 204 Rosacea Patients
    Regarding Rosacea Subgroups and Severity
 Alireza Ghanadan1, Kambiz Kamyab1, Vahideh sadat Azhari2, Shahriar Haddady Abianeh3,
         Elaheh Darzi2, Yasamin Kalantari2,4, Amir Abbas Peymanfar2, Ifa Etesami2,4


1 Department of Pathology, Razi Hospital, Tehran University of Medical Sciences, Tehran, Iran
2 Department of Dermatology, Razi Hospital, Tehran University of Medical Sciences, Tehran, Iran
3 Department of Plastic Surgery, Razi Hospital, Tehran University of Medical Sciences, Tehran, Iran
4 Autoimmune Bullous Diseases Research Center, Tehran University of Medical Sciences, Tehran, Iran



Key words: diagnosis, pathology, Rosacea, severity, subgroup
Citation: Ghanadan A, Kamyab K, Azhari VS, et al. Clinicopathological Survey of 204 Rosacea Patients Regarding Rosacea Subgroups
and Severity. Dermatol Pract Concept. 2023;13(3):e2023182. DOI: https://doi.org/10.5826/dpc.1303a182
Accepted: February 24, 2023; Published: July 2023
Copyright: ©2023 Ghanadan et al. This is an open-access article distributed under the terms of the Creative Commons
Attribution-NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted
noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited.
Funding: None.
Competing Interests: None.
Authorship: All authors have contributed significantly to this publication.
Corresponding Author: Ifa Etesami, Razi Hospital, Vahdat-e- eslami square, Tehran, Iran zip code: 1199663911,
number: 00989125665779, Email: Ifa.etesami@gmail.com




  ABSTRACT             Introduction: Few studies have evaluated the histopathological characteristics of clinical rosacea sub-
                       types in detail.
                       Objectives: To assess rosacea histopathological features in correspondence to clinical subgroups.
                       Methods: The histopathological findings of 204 rosacea patients were analyzed retrospectively and
                       were compared among clinical subtypes.
                       Results: Thirt-Two Percent of patients were male and 68% were female. Seventy-three patients had
                       erythematotelangiectatic rosacea (ETR) and 110 had papulopustular rosacea (PPR), 12 were ETR +
                       PPR, 4 ocular, 2 phymatous, and 3 had Morbihan’s edema. Perivascular and perifollicular lympho-
                       histiocytic infiltration, perifollicular exocytosis, follicular spongiosis, and ectatic vessels were almost
                       found in all subtypes. Solar elastosis was higher in ETR. Spongiosis, exocytosis of inflammatory cells
                       into epidermis, acanthosis, and granulomatous reaction were higher in PPR. Inflammatory cells exocy-
                       tosis was more in PPR and phymatous. Demodex folliculorum was identified in 27% of ETR, 33.6%
                       of PPR, 50% of phymatous, one ocular patient, and none of Morbihan edema. Demodex brevis were
                       found in 5% of ETR, 3% of PPR, and 50% of phymatous. Demodex brevis not folliculorum was more
                       in phymatous. Spongiosis was the most common finding in ocular rosacea.
                       Conclusions: Spongiosis, exocytosis of inflammatory cells, and granulomatous reactions were more
                       in PPR. Solar elastosis was more in ETR. Histopathological findings were compatible with clinical
                       subgroups.



Original Article | Dermatol Pract Concept. 2023;13(3):e2023182                                                                       1
Introduction                                                       a biopsy was taken from an unknown site (papule or patch
                                                                   not mentioned) the sample was excluded.
Rosacea is a chronic inflammatory skin disorder with a prev-          We asked one dermatopathologist to determine both epi-
alence of approximately 10% [1]. Rosacea is classified into        dermal and dermal changes that were present in specimens.
four major subtypes, based on clinical findings: erythema-         Epidermal changes evaluated were parakeratosis, hyperker-
totelangiectatic (ETR), papulopustular (PPR), phymatous            atosis, spongiosis, epidermal exocytosis, and interface der-
rosacea (PHYR), and ocular rosacea (OR) [2,3]. ETR is              matitis. Dermal changes involved solar elastosis, vascular
characterized by varying degrees of facial erythema and tel-       changes, papillary dermal edema, perivascular or perifollicu-
angiectasia. PPR is presented by facial erythema and a vari-       lar inflammatory infiltration, exocytosis of inflammatory cells
able number of inflammatory papules and pustules. PHYR             into hair follicles, follicular spongiosis, and granulomatous
presents with tissue hypertrophy, skin thickening, and seba-       reactions. Two main patterns of inflammation were defined
ceous gland hypertrophy, and ocular rosacea is presented           as perivascular or perifollicular inflammation. The severity
by nonspecific eye symptoms such as dryness, foreign body          of inflammation was scored between 0 and 3 (0 absence
sensation, tearing, and itching or signs such as blepharitis,      of infiltration; 1, faint infiltration; 2, moderate infiltration;
conjunctivitis, chalazion, and hordeolum. The pathogenesis         and 3, intense infiltration). The specimens were evaluated
of rosacea is not fully understood but it is believed to be        in terms of Demodex mite presence. The histopathological
a complex interaction between genetic, immunologic, and            findings were compared between subtypes. SPSS version 18
neurovascular factors that increase the susceptibility of indi-    was used to analyze the data statistically. The comparison of
viduals to environmental triggers such as UV radiation and         certain histopathological findings between rosacea subtypes
Demodex [4,5].                                                     was made by using the chi-square test or Fisher exact test.
                                                                   Informed consents were obtained from patients.

Objectives
Few studies are available regarding the clinical and histo-
                                                                   Results
pathological findings in rosacea. Previous studies demon-          Clinical Data
strated that although the intensity of inflammation especially
                                                                   The study included 204 rosacea patients with a mean age
perifollicular lymphohistiocytic infiltration was higher in
                                                                   of 42.5 years. Sixty-five (32%) patients were male and 139
PPR than ETR, there is no specific histological pattern that
                                                                   (68%) were female. Seventy-three patients (36%) had ETR,
can be diagnostic for any rosacea subtype [6,7]. The goal of
                                                                   110 patients (54%) had PPR, 12 patients (6%) had both
this study was to determine and compare the histopatholog-
                                                                   ETR and PPR, 4 patients had ocular rosacea, 2 of them had
ical findings of rosacea subtypes.
                                                                   PHYR rosacea and 3 patients had Morbihan edema. All ro-
                                                                   sacea subtypes were more common in females (M/F=1/2) ex-
Methods                                                            cept ocular rosacea which was more seen in males (M/F=3/1)
                                                                   (Table 1) (Figures 1, 2 and 5).
In this study, the out-patient clinic database was assessed ret-
rospectively and 204 patients diagnosed with rosacea during
                                                                   Rosacea Clinical Severity
2012-2018 that had a biopsy specimen available were en-
                                                                   Regarding the severity of ETR patients, 42.5 % (31/73) had
rolled. Rosacea diagnosis was made according to the Na-
                                                                   grade 1, 42.5 % (31/73) had grade 2, and 15.06 % (11/73)
tional Rosacea Society (NRS) Expert Committee based on
                                                                   had grade 3 of the disease. In terms of PPR patients, 21 %
the clinical findings such as flushing, permanent erythema,
                                                                   (23/110) had grade 1, 62.72 % (69/110) had grade 2, and
papules and pustules, telangiectasia, ocular findings, and
                                                                   16.4% (18/110) had grade 3. In patients with ETR + PPR,
phymatous changes. Demographic data were gathered from
                                                                   25 % (3/12) had grade 1, 58.3 % (7/12) had grade 2, and
medical records of our database including sex, age, rosacea
                                                                   16.7 % (2/12) had grade 3.
subtype, and severity. The four rosacea subtypes were ETR,
PPR, PHYR, and OR defined by a modified NRS classifi-
cation system [2]. The severity was defined based on estab-        Clinicopathological Correlation
lished criteria. The severity of features such as erythema,        The histopathological features of patients based on the three
papules, and pustules or telangiectasia was scored as ab-          main clinical subtypes are summarized in Table 2.
sent (grade 0), mild (grade 1), moderate (grade 2), severe            Spongiosis (N = 82, 42.05%), exocytosis of inflammatory
(grade 3) [3]. The specimens that were taken from erythem-         cells (N = 53, 27.17%), acanthosis (N = 36, 18.41%), and
atous patches in ETR and papules in PPR were analyzed. If          parakeratosis (N=27, 13.84%) in the manner of frequencies




2                                                                      Original Article | Dermatol Pract Concept. 2023;13(3):e2023182
               Table 1. Distribution of age stratification and sex ratio in all rosacea subtypes.
 Rosacea subtype               ETR
 (No)                          (73)      PPR (110)     ETR + PPR (12)       PHYR (2)      OR (4)    Morbihanedema (3)            Total
 Sex ratio (M/F)               1/3          1/9                  1/2           1/1          3/1               1/2                 1/2
 Age (yrs.)
 <35                          28%          33%               32%              50%          50%               67%                32.3%
 35-50                        34%          40%               38%               0           25%                0                 36.3%
 >50                          38%          27%               30%              50%         125%               33%                31.3%

ETR = erythematotelangiectatic rosacea; OR = ocular rosacea; PPR = papulopustular rosacea; PHYR = phymatous rosacea.



                                                                       were the most frequent epidermal changes in the three
                                                                       groups (ETR, PPR, ETR+PPR). Spongiosis (P value = 0.01)
                                                                       was significantly higher in the PPR group than ETR. Inter-
                                                                       face dermatitis was the least common finding among the 3
                                                                       subgroups. There was no significant difference between ro-
                                                                       sacea subtypes in other epidermal changes such as parakera-
                                                                       tosis and acanthosis.
                                                                           The most frequent dermal findings in both groups were
                                                                       ectatic vessels (92% in ETR, 95.5% in PPR), solar elastosis
                                                                       (63% in ETR subtype, 44% in PPR subtype), follicular exo-
                                                                       cytosis (53% ETR, 61% PPR), and follicular spongiosis (57%
                                                                       ETR and 63% PPR). Both perivascular and perifollicular lym-
Figure 1. Papulopustular rosacea. Papules, pustules and erythema
                                                                       phohistiocytic infiltration were commonly found in ETR and
on the face.
                                                                       PPR subtypes. Of note, score 1 perivascular infiltration was
                                                                       significantly more common in ETR subtype (42.5%) than PPR
                                                                       (21%) (P value = 0.03), score 2 and 3 of perivascular infiltra-
                                                                       tion though more common in PPR group than ETR but was
                                                                       not statistically significant. Although perifollicular infiltration
                                                                       was commonly found in both subtypes, score 3 of perifollicu-
                                                                       lar lymphohistiocytic infiltration was significantly higher in the
                                                                       PPR subtype (P value = 0.001). Solar elastosis was significantly
                                                                       more common in the ETR than PRP group (P -value = 0.003).
                                                                           Non-specific granulomatous reactions were significantly
                                                                       more common among PPR patients rather than ETR patients
                                                                       (P value = 0.04). Neutrophilic, eosinophilic, and plasma cell
                                                                       infiltration though more commonly found in PPR than ETR
                                                                       subtype but statistically, no difference was detected. Mast
                                                                       cell infiltration was more common in ETR than PPR but not
                                                                       statistically significant.
                                                                           Demodex mites were detected in 68 patients comprised
                                                                       of 23 patients with ETR, 39 patients with PPR, 4 with both
                                                                       ETR and PPR, and 2 with ocular rosacea. No correlation
                                                                       between the type of Demodex and histomorphologic find-
                                                                       ings is identified; Demodex brevis but not folliculorum was
                                                                       significantly more frequent in phymatous patients (Figure 3).
                                                                       The frequency of two Demodex brevis and Demodex fol-
                                                                       liculorum in ETR and PPR subtypes are shown in Table 2.
                                                                       The frequency of Demodex mites showed no difference be-
Figure 2. Erythematotelangiectatic rosacea. Persistent erythema and    tween groups. The association of Demodex mite frequency
telangiectasia of the cheek.                                           and sebaceous hyperplasia, follicular exocytosis, follicular




Original Article | Dermatol Pract Concept. 2023;13(3):e2023182                                                                           3
Table 2. The histopathological features of rosacea patients based on the three main clinical subtypes.
                                                    ETR subtype          PPR subtype           ETR + PPR subtype
 Histopathologic findings                           (N=73) N (%)        (N=110) N (%)            (N=12) N (%)              P value
 Epidermal changes
 Parakeratosis                                         9 (12.3)            17 (15.5)                  1 (8.3)               0.58
 Hyperkeratosis                                         2 (2.7)              4 (3.6)                   0 (0)                0.12
 Spongiosis                                            24 (33)              56 (51)                   2 (17)                0.01
 Acanthosis                                           10 (13.7)             26 (24)                    0 (0)                0.14
 Exocytosis of inflammatory cells                     14 (19.2)            38 (34.5)                  1 (8.3)               0.09
 Interface dermatitis                                    0 (0)               2 (1.8)                   0 (0)                0.61
 Dermal changes
 Papillary dermal edema                               12 (16.4)            18 (16.4)                 2 (16.7)               0.69
 Solar elastosis                                       46 (63)              48 (44)                   9 (75)                0.003
 Vascular proliferation or ectatic vessels             67 (92)            105 (95.5)                  11 (92)               0.58
 Perivascular lymphohistiocytic infiltration
    Score 1 (mild)                                    31 (42.5)             23 (21)                   3 (25)                0.03
    Score 2 (moderate)                                31 (42.5)            63 (57.3)                  7 (59)                0.16
    Score 3 (severe)                                  10 (13.7)            18 (16.4)                 2 (16.7)               0.92
 Perifollicular lymphohistiocytic infiltration
    Score 1 (mild)                                     32 (44)              23 (21)                   3 (25)                0.22
    Score 2 (moderate)                                 28 (38)             38 (34.5)                  6 (50)                0.78
    Score 3 (severe)                                   9 (12.3)            39 (35.5)                 2 (16.7)               0.001
 Follicular exocytosis                                39 (53.4)              6 (61)                   8 (67)                0.69
 Follicular spongiosis                                42 (57.5)            70 (63.6)                 8 (66.7)               0.84
 Demodex brevis                                         4 (5.5)              4 (3.6)                   0 (0)                0.56
 Demodex folliculorum                                  19 (26)              37 (34)                   4 (33)                0.74
 Folliculitis                                           8 (11)              23 (21)                  2 (16.7)               0.37
 Sebaceous hyperplasia                                 9 (12.3)              5 (4.5)                  1 (8.3)               0.25
 Granulomatous reaction                                 5 (6.8)            27 (24.5)                  3 (25)                0.04*
 Eosinophil infiltration                              13 (17.8)             26 (24)                   3 (25)                0.79
 Neutrophil infiltration                              18 (24.7)            37 (33.6)                  3 (25)                0.62
 Mast cell infiltration                                37 (51)              54 (49)                  7 (58.3)               0.59
 Plasma cell infiltration                              16 (22)             32 (29.1)                 2 (16.7)               0.44
 Melanin incontinence                                 10 (13.7)             10 (9.1)                  1 (8.3)               0.77

ETR = erythematotelangiectatic rosacea; PPR = papulopustular rosacea.



spongiosis, folliculitis, and deep infiltration was studied.        compared the histopathological findings of rosacea patients
Demodex mite frequency was significantly more common                according to their clinical subtypes. Histopathological fea-
in patients who had follicular spongiosis (Demodex positive         tures of various rosacea clinical subtypes are known to be
72% versus Demodex negative 57.4%, P value = 0.002), and            different. The ETR is distinguished mainly by dilated cap-
on the other side follicular exocytosis was negatively asso-        illaries and venules in the superficial dermis, perivascular
ciated with Demodex mite presence because, among those              and perifollicular lymphohistiocytic infiltration, and solar
patients who had follicular exocytosis, 48.6% were posi-            elastosis. The PPR is characterized by perifollicular lym-
tive for Demodex while 53.7% were negative for Demodex              phohistiocytic infiltration, follicular neutrophilic infiltra-
(P value = 0.024) as shown in (Figure 4).                           tion, superficial and deep dermal inflammation, and solar
                                                                    ­elastosis [8].

Conclusions                                                             Our data did not show any histopathological finding
                                                                    specific for clinical rosacea subtypes. Solar elastosis, ectatic
Only a few studies on the histopathological and clinical            vessels, perifollicular and perivascular lymphohistiocytic in-
correlation of rosacea are available [6,7]. In this study, we       flammation were found in all subtypes and not limited to


4                                                                        Original Article | Dermatol Pract Concept. 2023;13(3):e2023182
   Figure 3. Histopathologic findings. (A) Superficial dermal edema, solar elastosis and moderate perivascular lymphocytic infiltration
   (H&E × 10 original magnification). (B) Marked perifollicular granulomatous inflammation with lymphohistiocytic cells infiltrate
   admixed with giant cells (H&E × 10 original magnification). (C) Demodex folliculorum in follicular infundibulum and perifollicular
   lymphocytic inflammation (H&E × 10 original magnification). (D) Demodex brevis within sebaceous lobules (H&E × 20 original
   magnification).




   Figure 4. Association of follicular changes and Demodex mite.


Original Article | Dermatol Pract Concept. 2023;13(3):e2023182                                                                            5
    Figure 5. (A-C). Patient with phymatous rosacea.



any subtype. It is believed that follicular inflammation plays     feature of ETR [8], these findings are commonly seen in PPR
a critical role in rosacea pathogenesis [9]. In a previous study   too and are not specific to ETR.
perifollicular lymphohistiocytic infiltration was found in            Demodex mites were found in a high portion of rosacea
98% of patients with ETR and PPR equally [7]. In our study,        patients, the mite was present in more than 75% of rosacea
the frequency of perifollicular lymphohistiocytic infiltration     patients in a previous study [12]. It was believed that De-
was 94.5 % in ETR and 73.6 % in PPR with no signifi-               modex mite would play a role in rosacea pathogenesis by
cant statistical difference. Although grade 3 of perifollicular    inducing perifollicular inflammation. But the recently higher
lymphocytic infiltration was significantly higher in PPR than      frequency of perifollicular inflammation (more than 90%)
ETR in our study (P = 0.001), perifollicular infiltration is       in comparison to the lower frequency of Demodex mite, ap-
found in a high proportion of ETR as well and is not specific      proximately 40% in both ETR and PPR found by Lee et al.
for PPR. These findings, besides previous studies, suggest         led them to the conclusion that pathogenesis of rosacea can-
that perifollicular lymphohistiocytic infiltration is a nonspe-    not be only explained by Demodex mite [7]. In our study, the
cific finding that is found in all rosacea subtypes.               frequency of Demodex mite was 31.5% in ETR and 37.2%
    Based on our study, the most frequent epidermal changes        in PPR (both Demodex brevis and folliculorum) more in sup-
in both ETR and PPR subtypes were spongiosis, exocytosis           port of Lee et al study. Interestingly our study showed that
of inflammatory cells, acanthosis, and hyperkeratosis. Previ-      follicular spongiosis is significantly higher in mite positive
ous studies showed that acanthosis, parakeratosis, and exo-        patients and follicular exocytosis was significantly lower in
cytosis of inflammatory cells are statistically more common        mite negative patients suggesting that mite may be associated
in PPR, which is not supporting the findings of our study.         with follicular spongiosis, rather than follicular exocytosis.
The only epidermal change that was significantly more fre-         However, considering current literature, mites are not the
quent in PPR than ETR was spongiosis. Previously spongio-          only etiologic factor of follicular inflammation and other
sis was found in approximately 19% of patients irrespective        factors including dysregulated innate immune system and
of the rosacea subtype, but in our study spongiosis was 51%        neurogenic dysregulation besides extrinsic factors contribute
in PPR and 33% in ETR.                                             to the pathogenesis of rosacea [13].
    Sun exposure is known to play a role in rosacea pathogen-
esis and the proposed mechanisms are disrupting epidermal
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Original Article | Dermatol Pract Concept. 2023;13(3):e2023182                                                                              7
