Dermatology: Practical and Conceptual Original Article | Dermatol Pract Concept. 2023;13(3):e2023129 1 Interstitial Granulomatous Dermatitis and Palisaded Neutrophilic Granulomatous Dermatitis: Retrospective Clinicopathological Analysis of 16 Cases Ebru Sarıkaya Tellal1, Dilara Ilhan Erdil1, Muge Gore Karaali2, Ayse Esra Koku Aksu1, Erdemir VA3, Asude Kara Polat1, Cem Leblebici4 1 Department of Dermatology, University of Health Science (HSU) Istanbul Training and Research Hospital, Istanbul, Turkey 2 Department of Dermatology, Irmet International Hospital, Tekirdag, Turkey 3 Department of Dermatology, Göztepe Training and Research Hospital, Medeniyet University, Istanbul, Turkey 4 Department of Pathology, University of Health Science (HSU) Istanbul Training and Research Hospital, Istanbul, Turkey Key words: granulomatous dermatitis, interstitial granulomatous dermatitis, palisaded neutrophilic and granulomatous dermatitis, reactive granulomatous dermatitis Citation: Sarıkaya Tellal E, Ilhan Erdil D, Gore Karaali M, et al. Interstitial Granulomatous Dermatitis and Palisaded Neutrophilic Granulomatous Dermatitis: Retrospective Clinicopathological Analysis of 16 Cases. Dermatol Pract Concept. 2023;13(3):e2023129. DOI: https://doi.org/10.5826/dpc.1303a129 Accepted: December 1, 2022; Published: July 2023 Copyright: ©2023 Sarıkaya Tellal 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: Muge Gore Karaali, MD, Irmet International Hospital, Tekirdag, Turkey. Tel: +9005303093328 E-mail: mugegore@hotmail.com Introduction: Reactive granulomatous dermatitis (RGD) is a new entity, which is highly associated with systemic disorders. There is scarce data regarding interstitial granulomatous dermatitis (IGD) and palisaded neutrophilic granulomatous dermatitis (PNGD). Objectives: We aimed to evaluate clinical and histopathological characteristics of IGD and PNGD as unified entities under the term of RGD. Methods: Observational, retrospective, single-center study of patients diagnosed with IGD and PNGD between 2012 and 2021 were included in the study. Results: Of 16 patients (14 females and 2 males) with RGD, 13 had IGD and 3 had PNGD with a mean age of 62.5 years. The most common clinical presentation was plaques 37.5% (N=6), followed by patches 25% (N=4). The most common localization of involvement was lower extremity 75% (N=12), followed by trunk and upper extremity. Multiple localization of involvement was determined in 75% (N=12) of patients. None of the patients had rope sign. Associated comorbidities such as ABSTRACT 2 Original Article | Dermatol Pract Concept. 2023;13(3):e2023129 Introduction Interstitial granulomatous dermatitis (IGD) and palisaded neutrophilic granulomatous dermatitis (PNGD) are reactive granulomatous inflammatory skin disorders which were recently proposed to be unified under the term of reactive granulomatous dermatitis (RGD). They are highly associated with systemic disorders with only few and recent large pa- tient population studies regarding the concept of RGD [1,2]. IGD and PNGD are uncommon clinicopathological en- tities with a wide spectrum of clinical manifestations, and also it can be difficult to establish clinical and pathological correlations of these diseases. IGD usually presents with er- ythematous to violaceous patches or plaques symmetrically located on the upper trunk or proximal limbs, and PNGD with plaques/papules/nodules sometimes painful with cen- tral ulceration or crust distributed on the extensor limbs [3,4]. Despite of initial reporting of classical presentation of IGD with rope sign (linear subcutaneous cords), it is seen rarely in the current reports [2]. Histopathologically a diffuse, interstitial and perivascu- lar, superficial and deep inflammatory infiltrate composed mainly of lymphocytes and histiocytes surrounding foci of collagen degeneration in the dermis with a limited number of neutrophils and eosinophils have been determined. Scarce in- terstitial mucin deposition can be present. IGD usually does not have leukocytoclastic vasculitis (LV). On the other hand, despite overlapping histopathological findings with IGD, PNGD biopsies are characterized by more intense neutro- philic infiltration, karyorrhexis, more degenerated collagen in dermis, palisading granuloma with or without LV com- pared with IGD. Interstitial granulomatous drug reaction is also a form of IGD can mimic PNGD and IGD both clini- cally and histologically with prominent eosinophilic infiltra- tion [2]. Associated comorbidities of RGD include autoimmune diseases (as the most common cause), malignancy and in- fections. It is reported in the literature that there are not any associated comorbidities at the time of the diagnose in up to 25% of patients however, concomitant disease may also occur after the diagnosis and so follow up is required [2,4]. Objectives To analyze the clinicopathological findings and the disease associations of RGD. Methods We conducted an observational, retrospective study for clin- ical and histopathological analysis of 16 patients diagnosed with IGD and PNGD between the years 2012 and 2021 by searching the database of the Pathology and Dermatology Departments of a tertiary center. The study has been ap- proved by the Institutional Review Board of the hospital. Previously defined histopathological criteria, including presence of histiocytic and lymphocytic infiltration through the dermis and surrounding with foci of degenerated col- lagen was used in the current study [2]. The presence of a “floating sign” was noted, which is the visible clefting in ab- normal collagen by the clusters of histiocytes. Mucin depos- its should be absent or moderate. Patients who did not meet these criteria, and who had alternative diagnosis (necrobio- sis lipoidica, granuloma annulare, interstitial granulomatous drug reaction) were excluded from the study. For clinical analysis, sex, age at the diagnosis, local- ization, characteristics of the cutaneous lesions, associated symptoms, medical comorbidities, medication use, labora- tory values and treatments were recorded. Results Clinical Findings This study included 16 patients (14 females; 2 males, fe- male:male ratio of 7:1) aged between 42 and 81 years (mean 62.5±11.1 years). Symptom duration ranged from 1 month to 30 months (mean 7.0 ± 8.3 months). The most common autoimmune diseases and malignancies were detected in 68.7% (N=11) of patients. In majority of biopsies (87.5%; N=14), there were lymphohistiocytic cell infiltration. Other accompanying cells were scarce neutrophils 31.2% (N=5) and eosinophils 31.2% (N=5). All of the biopsies had interstitially located lymphohistiocytic cell infiltration surrounding with swollen and degenerated collagen. Pali- saded pattern was determined in 18.7% (N=3) of patients and floating sign was seen in 18.7% (N=3) of biopsies. Conclusions: RGD is a rare entity and most patients with RGD had associated disorders such as autoimmunity or malignancy. There is overlapping between IGD and PNGD, therefore supporting the usage of umbrella term as reactive granulomatous dermatitis is compatible with the literature. Original Article | Dermatol Pract Concept. 2023;13(3):e2023129 3 presentation was isolated plaques 37.5%, followed by only patch 25%, papules and plaques in 12.5% patients, one patient with papule and one patient with macule, papule, purpura. “Rope sign” was not present in any of the patients. All lesions were violaceous and/or erythematous in color (Figure  1). Most common localization was lower extrem- ity (mainly medial thigh region) 75%, followed by trunk 50%, upper extremity 43.7%. Multiple site involvement was seen in 75% of patients. One patient had face and neck involvement. Mycosis fungoides (56.2%) was the most commonly dif- ferential diagnosis of IGD/PNGD. IGD/PNGD were among the pathological pre-diagnoses in only 25% of the patients. Associated autoimmune systemic disease or malignancy was observed in 12 patients (68.7%). Associated diseases of PNGD were autoimmune hepatitis in one patient, Sjögren syndrome in one patient, lung cancer and Churg Strauss syndrome in one patient. In a single patient IGD occurred as Wolf isotopic response after herpes zoster (Patient #13). Comorbidities of patients with IGD and PNGD were listed in Table 1. The drugs used by the patients for their associated diseases were listed in Table 1. All of these drugs were used by the patients for many years. In 31.2% of patients there were no associated disease despite of clinical and laboratory evaluation for an under- lying disorder; 12.5% of patients, had both ANA positivity and arthralgia. Rheumatoid factor (RF) positivity was seen in 18.7% of patients and C-ANCA was positive in a single patient. During the follow-up, one of the patients diagnosed with Sjogren syndrome and the other patient with history of thyroiditis was diagnosed with rheumatoid arthritis. Patients with RGD were treated with topical corticoste- roids and also underlying systemic diseases were treated. All the lesions resolved completely with topical therapy in about six months without recurrency in a mean of 39.8 month fol- low up. The clinical features of the 16 patients are summa- rized in Table 1. Histopathological Findings Epidermis was preserved in 82.7% of the biopsies. Others had hyperkeratosis, parakeratosis, acanthosis and mild in- creased pigmentation. In all biopsies, there were lympho- histiocytic cell infiltration. Other accompanying cells were scarce neutrophils (31.2%), eosinophils (31.2%) and plas- mocytes (12.5%). All of the biopsies had interstitially lo- cated lymphohistiocytic cell infiltration surrounding with swollen and degenerated collagen. Palisaded pattern with combination of interstitial pattern was observed in 18.7% of patients. Floating sign was detected in 18.7% of biop- sies. None of the biopsies had dermal fibrosis. Alcian blue staining demonstrated interstitial minimal mucin in 56% of the biopsies and moderate mucin in one case, remaining biopsies did not reveal mucin formation. Nuclear debris was seen in 31.2%, vasculitic changes such as fibrinoid Figure 1. Some clinical presentations of the patients. (A) Erythematous papules and plaques on the anterolateral abdomen. (B) Vio- laceous papules extending from inframammary region to lateral trunk. (C) Violaceous macules on the arm. (D) Violaceous plaque on the inner thigh. 4 Original Article | Dermatol Pract Concept. 2023;13(3):e2023129 Table 1. Clinical features of 16 patients diagnosed with interstitial granulomatous dermatitis (IGD) and palisaded neutrophilic granulomatous dermatitis (PNGD). Patient Nr. Sex Age (year) Time to Lesion Lesion Characteristics Localization of Lesions Associated Diseases/Drugs (if available) Final diagnosis 1 F 77 2 mo Erythematous plaques Trunk, lower extremity Hypertension (calcium channel blockers) IGD 2 F 42 2 mo Violaceous papules and plaques Upper extremity Rheumatoid arthritis (non-steroid anti- inflammatory drugs) IGD 3 F 58 1,5 mo Erythematous to violaceous papules and plaques Face,neck, upper extremity Autoimmune hepatitis (azathioprine) PNGD 4 F 66 9 mo Violaceous plaques Trunk, lower extremity Hypertension (thiazide diuretic+ angiotensin receptor blocker) IGD 5 F 58 4 mo Erythematous to violaceous plaques Upper extremity, lower extremity Thyroiditis, type 2 diabetes mellitus (levothyroxine) IGD 6 F 58 24 mo Violaceous macules, papules and petechies Lower extremity Sjögren syndrome PNGD 7 F 58 6 mo Violaceous plaques Upper extremity, trunk, lower extremity Tubulovillous adenoma with high dysplasia IGD 8 F 81 12 mo Erythematous plaques Upper and lower extremity Thyroiditis (levothyroxine) IGD 9 F 71 3 mo Erythematous patches Trunk, lower extremity Hypertension (thiazide diuretic+ angiotensin receptor blocker) IGD 10 F 68 2 mo Violaceous patches Lower extremity Hypertension (angiotensin-receptor blocker) IGD 11 M 44 3 mo Erythematous plaques Upper extremity, trunk Rheumatoid arthritis (colchicine) IGD 12 F 58 30 mo Erythematous patches Trunk, lower extremity Behçet disease (colchicine) IGD 13 F 69 1 mo Violaceous papules Trunk Rheumatoid arthritis IGD 14 F 50 6 mo Erythematous patches Trunk, lower extremity None IGD 15 M 71 1 mo Erythematous patches, plaques and nodules Upper and lower extremity Lung adenocarcinoma, Churg Strauss syndrome PNGD 16 F 71 6 mo Erythematous plaques and patches Trunk, lower extremity Thyroiditis, hypertension (levothyroxine, thiazide diuretic) IGD IGD = interstitial granulomatous dermatitis; mo = months; PNGD = palisaded neutrophilic granulomatous dermatitis. necrosis was seen in 12.5%, leukocytoclasis in 12.5% of patients. Leukocytoclastic vasculitis was determined in 12.5% of patients. Histopathological information of the 16 biopsies is summarized in table 2 and some examples are shown in Figure 2. Conclusions RGD is an umbrella term for IGD and PNGD, which are rarely seen dermatosis with a wide clinical spectrum. IGD and PNGD have overlapping clinical and histopathological Original Article | Dermatol Pract Concept. 2023;13(3):e2023129 5 Ta b le 2 . H is to p at h o lo gi ca l fe at u re s o f 1 6 p at ie n ts d ia gn o se d w it h i n te rs ti ti al g ra n u lo m at o u s d er m at it is a n d p al is ad ed n eu tr o p h il ic g ra n u lo m at o u s d er m at it is . P a ti e n t E p id e rm a l in v o lv e m e n t Ly m p h o h is ti o cy ti c ce ll i n fi lt ra ti o n Fl o a ti n g si g n M u ci n P a li sa d in g P a tt e rn Fi b ri n o id n e cr o si s V a sc u li ti s Le u k o cy to cl a si a N u cl e a r D e b ri s N e u tr o p h il E o si n o p h il 1 + + - m in im al - - - - - - - 2 - + - m in im al - - - - + + + 3 a + + - - + - - - + + + 4 - + + m in im al - - - - - - - 5 - + + - - - - - - - + 6 a - + - - + - - - + - - 7 - + - m in im al - - - - - - - 8 - + - m in im al - - - - - - - 9 - + - - - - - - - - - 1 0 - + - m o d er at e - - - - - - - 1 1 - + - m in im al - + + + + + + 1 2 - + + - - - - - - + - 1 3 - + - - - - - - - - - 1 4 - + - m in im al - - - - - - - 1 5 a + + - m in im al + + + - + + - 1 6 - + - m in im al - - - - - - + P N G D = p al is ad ed n eu tr o p h il ic g ra n u lo m at o u s D er m at it is .a P at ie n ts w it h P N G D . 6 Original Article | Dermatol Pract Concept. 2023;13(3):e2023129 and/or malignancy (lung adenocarcinoma) were accompa- nied in all (100.0%) PNGD patients, in 7 of 13 (53.8%) patients with IGD had autoimmunity and 1 (7.7%) had malignancy (tubulovillous adenoma with high dysplasia). Neutrophilic infiltration was determined in all patients with palisading pattern and all of them were associated with auto- immunity or malignancy. However, we could not detect any clinical and/or histopathological data that can definitely dis- tinguish between these two entities due to a small number of PNGD patients and overlapping features of IGD and PNGD. For this reason, the term proposed as RGD in the current studies will be appropriate. Comorbidities associated with our patients were similar to the literature (60-76%) [1,2,4]. In one 69-year-old female patient with a history of herpes zoster, IGD developed in the same localization after one month. We evaluated this patient as Wolf’s isotopic response. One patient with Wolf isotopic response was reported in the literature. This patient was an 11-year-old boy diagnosed with IGD possibly to herpes zoster [11]. Autoimmune hepatitis associated with IGD was previously reported [3,12,13]. In our series, the patient with findings. Therefore, more extensive reports on these diseases are needed. Reported clinical presentations of RGD in the previous studies are annular plaques, erythematous-violaceous pap- ules or nodules [4,5], non-scaly annular plaques (similar to most of our patients) [4,6,7], linear-shaped plaques [8,9] and arciform-non scaly nodules [10]. Most of our patients pre- sented with MF like, erythematous to violaceous plaques on the sun-protected sites such as axilla, lateral chest or inner thighs. Since RGD is a rare disease, this diagnosis can be un- derestimated by clinicians, thus in only 25% of the patients in our study, pre-diagnosis of IGD/PNGD was possible due to a wide spectrum of presentations. According to our results RGD should be considered in the differential diagnosis of plaque lesions on sun-protected areas. It has been reported that the rope sign is rarely seen in studies, similar to these studies, this finding was not found in any of the patients in our study, despite of initial reporting of classical presentation of IGD with rope sign [2]. Due to possible accompanying diseases, correct and early diagnosis of RGD is important. In our study, autoimmunity Figure 2. Some histopathological examination of the skin of patients. (A) Interstitial lymphohistiocytic infiltrate with collagen degeneration- interstitial granulomatous dermatitis subtype (H&E, ×100). (B) Collagen degeneration and “floating sign” with lym- phohistiocytic infiltrate (H&E, ×200). (C) Palisading granulomas accompanied by neutrophils, lymphohistiocytic infiltration, collagen degeneration (H&E, ×200). (D) Palisading granulomas accompanied by neutrophils, lymphohistiocytic infiltration, collagen degen- eration (H&E, ×400). 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DOI: 10.1590/abd1806-4841.20153263. PMID: 26131871. PMCID: PMC4516102. 6. Altemir A, Iglesias-Sancho M, Sola-Casas MLÁ, Novoa-Lamazares L, Fernández-Figueras M, Salleras-Redonnet M. Interstitial gran- ulomatous dermatitis following tocilizumab, a paradoxical reaction? Dermatol Ther. 2020;33(6):e14207. DOI: 10.1111 /dth.14207. PMID: 32816393. 7. Wang Y, Wu Y, Zheng Z, Bai Y, Cui Y. Interstitial granulomatous dermatitis associated with primary biliary cirrhosis. J Dermatol. 2018;45(1):112-113. DOI: 10.1111/1346-8138.13778. PMID: 28225148. 8. Kim YS, Lee JH, Lee JY, Park YM. Interstitial Granulomatous Dermatitis Associated with Rheumatoid Arthritis. Ann Der- matol. 2016;28(3):395-397. DOI: 10.5021/ad.2016.28.3.395. PMID: 27274645. PMCID: PMC4884723. 9. Verneuil L, Dompmartin A, Comoz F, Pasquier CJ, Leroy D. Interstitial granulomatous dermatitis with cutaneous cords and arthritis: a disorder associated with autoantibodies. J  Am Acad Dermatol. 2001;45(2):286-291. DOI: 10.1067 /mjd.2001.114577. PMID: 11464193. 10. Rato M, Gil F, Monteiro AF, Aranha J, Tavares E. Interstitial gran- ulomatous dermatitis in a patient with chronic hepatitis C and mixed cryoglobulinemia. Dermatol Online J. 2018;24(1):13030/ qt3x33s9m7. PMID: 29469770. 11. Takenoshita H, Yamamoto T. Granulomatous isotopic re- sponse possibly to herpes zoster in childhood. J Dermatol. 2014;41(7):651-652. 12. Lee KJ, Lee ES, Lee DY, Jang KT. Interstitial granulomatous dermatitis associated with autoimmune hepatitis. J Eur Acad Dermatol Venereol. 2007;21(5):684-685. DOI: 10.1111/j.1468 -3083.2006.01982.x. PMID: 17447986. 13. Szepetiuk G, Lesuisse M, Piérard GE, Quatresooz P, Piérard- Franchimont C. Autoimmunity-related granulomatous der- matitis in association with hepatitis. Case Rep Dermatol. 2012;4(1):80-84. DOI: 10.1159/000337894. PMID: 22649335. PMCID: PMC3362185. 14. Corneli P, di Meo N, Zalaudek I, et al. Interstitial granuloma- tous dermatitis as primary manifestation of marginal zone lym- phoma. Int J Dermatol. 2020;59(11):e412-e414. DOI: 10.1111 /ijd.14981. PMID: 32662885. 15. Kim SM, Cho SH, Lee JD, Kim HS. Interstitial Granulomatous Dermatitis in a Patient with Prostate Cancer. Ann Dermatol. PNGD was accompanied by autoimmune hepatitis. In liter- ature, other diseases which may accompany were autoim- mune disorders such as; rheumatoid arthritis [3,4], systemic lupus erythematosus [1,3,4,16], autoimmune thyroiditis, primary biliary cirrhosis [7], malignancies such as hema- tological or solid cancers [14,15], infections such as HCV and related cryoglobulinemia [10], coccidiomycosis [17] or medications [4,5]. In 31.2% of patients, there were no associated autoimmunity or malignancy despite of clinical and laboratory evaluation for an underlying disorder. Due to high association with systemic disorders, follow-up of the patient for the possible development of autoimmunity or malignancy is important despite of having no associated features at time of diagnosis. In addition to reported comorbidities, we had a patient with Behçet disease and IGD in our case series. When we search for the literature, Behçet’s disease accompanies only two patients with PNGD [18,19]. Kim et al. reported a 32-year-old female with papular lesions on legs [18]. Shin et al. reported a 60-year-old female with also popular lesions on extremities, buttocks, and ear lobes [19]. In our study the patient with IGD and Behçet disease was 58-year-old female, and her lesions were erythematous patches on her trunk and legs. Angiotensin receptor antagonists, thiazide diuretics, cal- cium channel blockers are thought to be associated with in- terstitial granulomatous drug reaction [3]. Like mentioned in methods, interstitial granulomatous drug reaction was excluded from the study. However, when the drugs used by the patients, especially the antihypertensive drugs were eval- uated, they were not considered to be associated with IGD development in this study, as the duration of the drugs were more than four years in our study. RGD is a rare clinicopathological entity. This is one of the larger case series presenting new disease associations. Since there is a high association with systemic disorders, fol- low up of patients is required. Due to overlapping features between IGD and PNGD, the term proposed as RGD in the current studies will be appropriate. References 1. Bangalore Kumar A, Lehman JS, Johnson EF, et al. Reactive Granulomatous Dermatitis as a Clinically Relevant and Unifying Term: Retrospective Review of Clinical Features, Associated Sys- temic Diseases, Histopathology, and Treatment for a Series of 65 Patients at Mayo Clinic. 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Interstitial granulomatous der- matitis associated with systemic lupus erythematosus: case re- port and review of the literature. Lupus. 2016;25(2):209-213. DOI: 10.1177/0961203315604908. PMID: 26385222. 17. DiCaudo DJ, Connolly SM. Interstitial granulomatous dermatitis associated with pulmonary coccidioidomycosis. J Am Acad Der- matol. 2001;45(6):840-845. DOI: 10.1067/mjd.2001.117522. PMID: 11712027.