Dermatology: Practical and Conceptual Letter | Dermatol Pract Concept 2020;10(3):e2020057 1 Dermatology Practical & Conceptual Introduction Generalized eruptive histiocytosis (histiocytoma) (GEH) is a very rare cutaneous non-Langerhans cell histiocytosis, char- acterized by recurrent crops of small red to brown papules. Case Presentation A 58-year-old woman with an 8-month history of hundreds of symmetric yellow-brown flat-topped papules (Figure 1, A and B) came for dermatologist consultation. The lesions appeared in crops localized on the trunk and extremities. It was believed that the skin lesions were caused by trazodone and lithium, which were being used in the treatment of bipo- lar disorder. The medications were stopped, but the lesions continued to develop. Routine blood and urine analyses were unremarkable. Dermoscopy was performed on one representative lesion on the lower leg. The histology was consistent with the diag- nosis of GEH (Figure 1, C-G). After GEH diagnostics, additional investigations were done. Hyperprolactinemia, hypercorticism, and hypofunction of the thyroid gland were detected. Abdominal ultrasonogra- phy and MRI of the sella turcica and hematological studies with biopsy of the bone marrow were without pathological findings. Three years from the first onset, the skin lesions mostly resolved, leaving hyperpigmented macules. Literature Review Seventy-four cases (58.1% males) of GEH have been pub- lished, including 24 (32.4%) children (Table 1 and Sup- plementary References, which are appended to the pdf). The average age was 30.5 years. In adults and children the average age was 43.2 years and 4.2 years, respectively. The most frequent body site was the trunk (86%), followed by the extremities (79%). The lesions resolved spontaneously from 2 weeks onward, but in rare cases persisted for 20 years. In 4 children the lesions evolved into xanthoma disseminatum; in 1 child the lesions coexisted with juvenile xanthogranuloma. Dermoscopy of Generalized Eruptive Histiocytosis: Case Report and Brief Review of the Literature Danijela Dobrosavljevic,1,2 Jovana Majstorovic,1 Martina Bosic2,3 1 Clinic of Dermatovenereology, Clinical Centre of Serbia, Belgrade, Serbia 2 Faculty of Medicine, University of Belgrade, Serbia 3 Institute of Pathology, University of Belgrade, Serbia Key words: generalized eruptive histiocytosis, non-Langerhans cell histiocytosis, histiocytic disorders, dermoscopy, dermatoscopy Citation: Dobrosavljevic D, Majstorovic J, Bosic M. Dermoscopy of generalized eruptive histiocytosis: case report and brief review of the literature. Dermatol Pract Concept. 2020;10(3):e2020057. DOI: https://doi.org/10.5826/dpc.1003a57 Accepted: February 27, 2020; Published: June 29, 2020 Copyright: ©2020 Dobrosavljevic et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: None. Competing interests: The authors have no conflicts of interest to disclose. Authorship: All authors have contributed significantly to this publication. Corresponding author: Danijela Dobrosavljevic, MD, PhD, Clinic of Dermatovenereology, Pasterova 2 St, Clinical Centre of Serbia and Faculty of Medicine, University of Belgrade, Belgrade, Serbia. Email: danijela_dobrosavljevic@yahoo.co.uk https://doi.org/10.5826/dpc.1003a57 mailto:danijela_dobrosavljevic@yahoo.co.uk 2 Letter | Dermatol Pract Concept 2020;10(3):e2020057 (Table 1). In preschool children, diabetes insipidus should be suspected if GEH evolves into xanthoma. In adults, hemato- logical follow-up is suggested. Clinical differential diagnosis of GEH includes other his- tiocytic disorders such as Letterer-Siwe disease, juvenile xan- thogranuloma (multiple), papular xanthoma, and progressive nodular histiocytosis. Exanthema due to medications and viruses, with separate entity Gianotti-Crosti syndrome and early eruption of guttate psoriasis, are main differentials as well. Although GEH is a benign, self-healing eruption of non-Langerhans cell lineage, follow-up is necessary. Two age groups of GEH patients are reported: up to 14 years and adults. Brain infiltrations and diabetes insipidus are reported in 3 (12.5%) children up to age 4 years with xanthomatous evolvement. In 5 (10.0%) of the published adult cases, hematological disorders of myeloid lineage such as acute monocytic/monoblastic leukemia (2 cases) or chronic myelomonocytic/eosinophilic leukemia (3 cases) are reported Figure 1. (A,B) Symmetric yellow-brown, flat-topped papules localized on the trunk (A) and extremities (B). (C) Dermoscopic finding: or- ange-yellow homogeneous pigmentation, delicate linear branching, and serpentine vessels. Solitary, red clods are present in some lesions. (D) Dermoscopic finding after 3 months: partially regressed lesions reveal yellow background and linear serpentine vessels. (E) Focally dispersed small dermal granulomas composed of histiocytes and multinuclear giant cells with peripheral arrangement of nuclei (E,F) (H&E, ×100). (F) Focal emperipolesis is noted in giant cells (arrows) (H&E, ×400). (G) Positive immunohistochemical staining of CD68 in granulomas (magnification ×200). Immunohistochemically, granulomas presented with profile CD68+ CD163+/−, and CD1a−. Letter | Dermatol Pract Concept 2020;10(3):e2020057 3 Table 1. Clinical Characteristics of the Published Cases With Generalized Eruptive Histiocytosis (Histiocytoma) (GEH) Referencea Age at Onset (yrs)b Sex Location Course Associated Finding Wise (1919)c 22 M Trunk, proximal part of extremities Lasted 20 years None Glauberzon and Lebedeff (1952)c 34 F Disseminated Not defined None Calas et al (1959)c 52 M Face, trunk, extremities Not defined None Baccaredda-Boy (1960)c 33 M Trunk, extremities, face, mouth No data, died after 19 years Mutilating polyarthritis Herzberg (1961)c 30 F Trunk, extremities Spontaneous regression after 13 years Amenorrhea Winkelmann and Muller (1963) 51 F Trunk, extremities Number of lesions increased within 15 months Osteoarthritis Winkelmann and Muller (1963) 58 M Trunk, axillae, pubic area and penis, buccal mucosa Increasing in number within 4 years None Winkelmann and Muller (1963) 38 F Face, trunk, extremities Cleared gradually after 12 years None Cramer (1963) 25 M Disseminated Resistant to steroids None Pegum (1973) 42 M Trunk, extremities No regression after 2.5 years High cholesterol Sohi et al (1979) 49 M Generalized Regressed in a few months, then recurred 2 years later None Winkelmann (1980) 3 months F Extensor limbs, buttocks Persisted until at least 9 years old Glaucoma and uveitis Caputo et al (1981) 25 M Thorax, abdomen, inguinal fold, proximal extremities Resolved spontaneously in 4 years None Aso et al (1982) 4 M Disseminated Spontaneous regression of 80% lesions after 2 years None Arnold et al (1982) 32 M Disseminated Persisted for 20 years None Bobin et al (1983) 22 M Trunk, extremities Partial regression within 1 year None Idikio and Hogan (1983) 57 F Abdomen, pubic area, breasts, back, axillae, face Unchanged in 9 years Hyperlipidemia type IV Statham et al (1984) 66 F Trunk, extremities, nasal mucosa Death 18 months after the diagnosis from acute leukemia Acute leukemia of monoblastic/histiocytic origin Caputo et al (1987) 11 months M Trunk, neck, head, extremities Disappeared in 5 years None Caputo et al (1987) 11 months F Face, trunk Mostly regressed in 6 years None Caputo et al (1987) 10 months M Trunk, scrotum Mostly regressed in 2 years None Caputo et al (1987) 44 months F Trunk, axillae, face Mostly regressed in 3 years None (Table 1 continues) 4 Letter | Dermatol Pract Concept 2020;10(3):e2020057 Table 1. Clinical Characteristics of the Published Cases With Generalized Eruptive Histiocytosis (Histiocytoma) (GEH) (continued) Referencea Age at Onset (yrs)b Sex Location Course Associated Finding Shimizu et al (1987) 24 M Cheeks, later generalized Regressed in 1 year None Sigal-Nahum et al (1987) 7 F Face, buttocks, extremities Spontaneous regression and new crops within few months None Braun-Falco et al (1988) 19 M Trunk, axillary, face, throat Evolved into xanthoma disseminatum None Grob et al (1988) 25 M Face, axillary Eruption persisted 2 years None Umbert and Winkelmann (1989) 67 F Face, trunk, arms Slow progression within 9 years Hypothyroidism, normolipemic xanthelasma, polyclonal gammopathy Ashworth et al (1990) 21 M Disseminated, sparing mucosa 8 years continual progression of the disease Atopic dermatitis, asthma Saijo et al (1991) 14 F Trunk Within 14 months: partial regression with new lesions None Stables and MacKie (1992) 55 F Arms, trunk, upper thighs, face Present for at least 24 months None Izaki et al (1993) 1 M Face, neck, upper arms Persisted for next 5 years until spontaneous resolution None Goerdt et al (1994) 69 M Trunk, extremities Persisted for at least 5 years High cholesterol Repiso et al (1995) 4 M Face, trunk, proximal extremities Evolved into xanthoma disseminatum Developed diabetes insipidus and brain infiltrations Gibbs and O’Grady (1996) 41 M Face, arms, torso Lesions persisted for 9 years Diabetes mellitus type II Jang et al (1999) 3 months M Face, trunk, groin, upper and lower limbs Spontaneous regression within 2 months; no new lesions within 2 years None Matsushima et al (1999) 5 F Generalized Spontaneous regression within 8 months Rheumatic fever Wee et al (2000) 9 M Trunk, proximal extremities Spontaneous regression of some lesions with new crops None Marzano et al (2002) 33 F Trunk, extremities Resolved within 6 months None Wollenberg et al (2002) 13 F Abdomen, trunk Persisted for 3 years Coexistence with skin lesions proven to be indeterminate cell histiocytosis Klemke et al (2003) 59 M Trunk, neck, face, and thighs Improved under aplasiogenic regimen Acute monocytic leukemia Seward et al (2004) 55 M Trunk, extremities Several lesions resolved after cryotherapy None Deng et al (2004) 39 M Face, trunk, limbs Spontaneously resolved within 6 months Increased eosinophilia Mehravaran (2004) 53 F Trunk, upper extremities No follow-up None Tamiya et al (2005) 14 months F Trunk, extremities Spontaneously resolved within 1 month Immunoglobulin G, human herpesvirus 6 (Table 1 continues) Letter | Dermatol Pract Concept 2020;10(3):e2020057 5 Table 1. Clinical Characteristics of the Published Cases With Generalized Eruptive Histiocytosis (Histiocytoma) (GEH) (continued) Referencea Age at Onset (yrs)b Sex Location Course Associated Finding Vázquez-Blanco et al (2006) 64 M Trunk, extremities, mucous membranes Subsided after photochemotherapy, but reappeared None Kiliç et al (2006) 1 M Face, trunk, extremities Stable for 12 months, partial regression after 41 months None Lan Ma et al (2007) 32 F Trunk, extremities, face In 3 months resolved with PUVA Eosinophilia in peripheral blood and in bone marrow cytology Tang et al (2007) 36 F Trunk, abdomen, extremities After 8 years, spontaneous regression of some lesions observed None Fernández-Jorge et al (2007) 41 F Trunk and arms Spontaneously resolved in 11 months Hypercholesterolemia Bajaj and Iqbal (2008) 28 M Face, chest, axillae Resolved after 1 week with liquid nitrogen None Kwinter and DeKoven (2009) 53 F Face, neck, arms Resolved after 8 months with isotretinoin, then recurred None Chern et al (2010) 5 months F Face, trunk, arms, legs Spontaneously resolved in 6 months Mild leukocytosis Aggarwal et al (2010) 61 M Trunk, arms, legs Spontaneously resolved with relapses within 4 years None Sharath Kumar et al (2011) 23 F Face, trunk, arms, legs Minimal resolution, persisted 5 years None Attia et al (2011) 48 F Upper limbs and trunk Spontaneously resolved None Montero et al (2012) 80 M Trunk, abdomen Resolved after 6 months Chronic myelomonocytic leukemia Verma (2012) 10 M Hands, feet, trunk Coexistence with juvenile xanthogranuloma lesions None Cardoso et al (2013) 79 M Trunk, eyelids Spontaneously resolved in 2 months None Zamudio Vega et al (2013) 8 M Face, upper extremities 8 months unchanged None Shon et al (2013) 84 M Face, neck, arms Died after 4 months Chronic myelomonocytic leukemia Kazi et al (2014) 23 M Lower extremities No follow-up None Ghandi et al (2015) 28 F Face, trunk, extremities Spreading within 2 years None Ziegler et al (2015) 20 M Trunk, extremities Complete remission with imatinib FIP1L1-PDGFRA- positive chronic eosinophilic leukemia Hansel et al (2015) 60 M Trunk, extremities Remission with PUVA and topical corticosteroids None Mahajan et al (2015) 60 M Extremities No follow-up None Wilk et al (2016) 64 M Trunk, extremities Unchanged for several years None (Table 1 continues) 6 Letter | Dermatol Pract Concept 2020;10(3):e2020057 Conclusions Our case emphasizes the importance of dermoscopic exam- ination in the everyday practice of dermatologists. Further studies of skin histiocytic disorders are required in order to establish all dermoscopic criteria. Acknowledgment The authors thank Mrs. Ana Ivkovic from the Institute of Oncology and Radiology of Serbia, Belgrade, Serbia, and Mr. William Russell-Edu from the European Institute of Oncol- ogy, Milan, Italy, for providing scientific literature. References 1. Kaçar N, Demirkan N, Duygulu Ş. Generalized eruptive histiocy- tosis diagnosed in light of dermoscopic findings. Int J Dermatol. 2018;57(3):355-357. https://doi.org/10.1111/ijd.13867 2. Erricheti E, Stinco E. Dermoscopy in general dermatology: a practi- cal overview. Dermatol Ther (Heidelb). 2016;6(4):471-507. https:// doi.org/10.1007/s13555-016-0141-6 A case describing dermoscopy of GEH lesions resembling molluscum contagiosum in an infant has been published [1]. A homogeneous orange-yellow pattern with an erythematous border described as “setting-sun” was recognized. Histology revealed histiocytic cells with foamy xanthomatous cyto- plasm [1]. The dermoscopic finding in our case presented with orange-yellow homogeneous pigmentation, delicate linear branching, serpentine vessels, and solitary, red clods. Histology revealed histiocytic cells forming granulomas. The dermoscopic differential diagnosis of GEH is broad and encompasses juvenile xanthogranuloma, cutaneous sarcoidosis, necrobiosis lipoidica, granuloma annulare (pal- isading granuloma histological subtype), elastosis perforans serpiginosa, granulomatous rosacea, annular elastolytic giant cell granuloma, and rheumatoid nodules. Among infective diseases, lupus vulgaris, cutaneous leishmaniasis, borderline tuberculoid leprosy, and Majocchi granuloma are the most important differentials [2]. Combining clinical, dermoscopic, and histological findings is of greatest importance in any of the diseases mentioned. Table 1. Clinical Characteristics of the Published Cases With Generalized Eruptive Histiocytosis (Histiocytoma) (GEH) (continued) Referencea Age at Onset (yrs)b Sex Location Course Associated Finding Piney et al (2016) 28 M Face, trunk, extremities Resistant to imatinib, interferon alpha, anakinra; resolved after PUVA therapy Arthralgia Alperovich et al (2017) 3 F Trunk, face 6-month follow-up: CNS lesions-xanthomata Diabetes insipidus Arif et al (2017) 26 F Face, trunk, arms Persisted and coalesced within 3 months None Kar et al (2018) 6 F Face, axillae, trunk Spontaneously resolved None Kaçar et al (2018) 19 months F Diaper area, extremities, trunk Spontaneously resolved None Costin et al (2019) 24 F Trunk, neck and proximal upper extremities Unchanged after 1 year None Takahashi et al (2019) 1 M Trunk After 1 year partially regressed None Kobayashi et al (2019) 7 months M Neck, trunk, extremities 2-year follow-up; lesion evolved into xanthoma disseminatum; resistance to chemotherapy Diabetes insipidus aFull references are provided in the supplementary content, which is appended to the pdf. bAge is given in years except where indicated as months. cIn 1963 Winkelmann and Muller reported 3 cases of GEH, but some cases with cutaneous and histological abnormalities consistent with GEH were reported before their report, under different names (Sohi et al, Dermatologica. 1979;159(6):71-75; Bobin et al, Ann Dermatol Venereol. 1983;110(10):817-824). https://doi.org/10.1111/ijd.13867 https://doi.org/10.1007/s13555-016-0141-6 https://doi.org/10.1007/s13555-016-0141-6 Letter | Dermatol Pract Concept 2020;10(3):e2020057 7 Supplementary Material: Table 1 References 1. 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