Are You Confident of the Diagnosis?
Generalized eruptive histiocytoma (GEH) is a non-Langherhans cell histiocytosis (Table 1). These disorders share the same immunophenotypes but differ in clinical presentation, population affected, and disease course and prognosis.
Characteristic findings on physical examination
Adults present most commonly in the fourth to sixth decade and children prior to the age of 4. GEH is characterized by sudden onset of a generalized eruption of monomorphous papules. Lesions are neither pruritic nor painful and there are no systemic symptoms associated with the eruption. The lesions are not preceded by any inflammatory change and the past medical history and family history are usually non-contributory.
GEH presents with rapid onset of widespread, non-grouped, skin-coloured to blue-red round or oval firm papules on the face, trunk and proximal extremities (Figure 1),Figure 2.
Papules continue to erupt in recurrent crops with hundreds present at a time. The lesions tend to be symmetric in adults but can be more scattered and asymmetric in children. The eruption is asymptomatic, and mucous membrane involvement can occur occasionally in adults but has not been reported in children. Individual lesions do not tend to grow or change and regress 1 month up to 12 years after their onset. The lesions may continue to appear in crops for many years until there is spontaneous resolution with either complete disappearance of lesions or residual brown macules. The lesions do not scar. Once the lesions regress completely they do not tend to recur, however, relapses have been reported.
Expected results of diagnostic studies
Histopathology demonstrates benign and monomorphic-appearing lesions with a uniform dense infiltrate of non-xanthomatous histiocytes with scant nuclear chromatin and an abundant, light cytoplasm within the superficial and mid-dermis. There may be a few lymphocytes present within the infiltrate; occasionally multinucleate giant cells may also be found (Figure 3,Figure 4).
Specimens stain negatively for lipids, mucopolysaccharides and the Langerhans’ cell marker S100. Immunohistochemistry demonstrates positivity for Ki-M1p (a member of the CD68 marker family and the most reliable marker of non-Langerhans cell histiocytoses), HAM 56 and factor XIIIa and CD68. Electron microscopy demonstrates prominent dense bodies within the cytoplasm, occasional worm-like bodies and concentric laminated bodies often clustered together. There are no serologic tests that aid in the diagnosis of GEH.
The differential diagnosis for GEH includes urticaria pigmentosa (especially in children), sarcoidosis and the other non-Langerhans cell histiocytoses (Table 2), especially juvenile xanthogranuloma, xanthoma disseminatum, benign cephalic histiocytosis and indeterminate cell histiocytosis. Though they may at times appear clinically similar to GEH, juvenille xanthogranuloma and xanthoma disseminatum can be differentiated by histopathology by the presence of xanthomatized histiocytes as well as Touton giant cells in the former.
Benign cephalic histiocytosis can be difficult to distinguish from GEH on histopathology, but clinically it tends to occur in children with lesions only on the head and neck. Indeterminate cell histiocytosis can be clinically indistinguishable, however, histopathology demonstrates features of both Langerhans and non-Langerhans cell histiocytoses and thus lesions are S100 and CD1a positive. Lesions of urticaria pigmentosa demonstrate a positive Darier sign (urticate when rubbed) and histopathology shows mast cells, not histiocytes. Sarcoidosis demonstrates non-caseating naked granulomas on histopathology.
Table I. Non-Langerhans Cell Histiocytoses
|Generalized eruptive histiocytoma|
|Benign cephalic histiocytoma#|
|Indeterminate cell histiocytosis|
|Progressive nodular histiocytosis|
|Sinus histiocytosis with massive lymphadenopathy^|
# Some belive that benign cephalic histiocytoma is a variant of generalized eruptive histiocytoma.
*Some believe that papular xanthoma is a variant of juvenile xanthogranuloma.
^ Some classify necrobiotic xanthogranuloma and sinus histiocytosis with massive lymphadenopathy as indeterminate cell histiocytoma.
Table II. Clinical, Histopathologic and Immunohistochemical Variations in Non-Langherhans Cell Histiocytoses
|Non-Langerhans Cell Histiocytosis||Clinical Presentation||Pathology||Immunohistochemistry|
|GEH||Generalized, symmetric, flesh-colored to blue -red papules on the face, trunk and proximal extremities associated with spontaneous resolution||Monomorphous infiltrate of vacuolated histiocytes staining negatively for lipids and mucopolysaccharides||CD68+, HAM56+, Factor XIIIa+|
|Benign Cephalic Histiocytosis||Multiple, nongrouped, smooth, red-brown papules on the head and neck commonly occurring in children; mucous membranes are spared||Monomorphous dermal infiltrate of vacuolated histiocytes with intracytoplasmic comma-shaped bodies||CD68+, HAM56+, Factor XIIIa+|
|Juvenile Xanthogranuloma||Single or multiple well-dermarcated, tan-orange, firm papules commonly on the head and neck||Diffuse polymorphous infiltrate with vacuolated, xanthomatized and spindle shaped histiocytes as well as Touton giant cells||CD68+, HAM56+, Factor XIIIa+/-|
|Papular Xanthoma||Generalized well-dermacated tan-orange firm papules or nodules, similar in appearance to juvenile xanthogranuloma but rapidly become xanthomatous||Histiocytes with predominence of xanthomatized cells, foam cells and Touton giant cells within the dermis, scant inflammatory infiltrate||CD68+, HAM56+, Factor XIIIa+|
|Xanthoma Disseminatum||Disseminated red-yellow to red-brown papules||Scalloped histioycytes and xanthomatous histiocytes, Touton giant cells||CD68+, HAM56+, Factor XIIIa+|
|Indeterminate Cell Histiocytosis||Solitary or generalized firm red-brown papules that wax and wane with eventual resolution; no mucous membrane involvement||Monomorphous infiltrate of vacuolated mononuclear histiocytes throughout dermis, lymphocytic infiltrate||CD68+, HAM56+, Factor XIIIa+, S100+, CD1a+|
|Multicentric Reticulohistiocytosis||Yellow-pink to yellow-brown papulonodules grouping into plaques on hands, over joints and on the head, often with mucous membrane involvement. Solitary and diffuse variants exist.||Large mononucleated and multinucleated histiocytes with eosinophilic cytoplasm and giant cells||CD68+, HAM56+, factor XIIIa +/-|
|Progressive Nodular Histiocytosis||Generalized yellow-pink papules and nodules on face and trunk with mucous membrane involvement||Foamy macrophages in superficial lesions, monomorphous infiltrate of spindle-shaped histiocytes in deep lesions||CD68+, HAM56-, Factor XIIIa+|
|Necrobiotic Xanthogranuloma||Red-orange papulonodules that enlarge into plaques, atrophy and ulcerate most often involving the face, but also trunk and extremities||Lymphocytes, epitheloid cells, foam cells and Touton giant cells throughout the dermis and subcutis with areas of necrosis||CD68+|
|Sinus Histiocytosis with Massive Lymphadenopathy||Cutaneous lesions in 10% of patients, multiple, widespread yellow to red-brown macules, papules and nodules that become ulcerated||Dermal histiocytes with large nuclei and pale cytoplasm, multinucleate cells may be present as well as a mixed inflammatory infiltrate||
CD68+, factor XIIIa +/-, S100+, CD1a-
Who is at Risk for Developing this Disease?
GEH is a very rare disease with approximately 35 cases reported to date. It affects both adults and children, though it is more common in adults. GEH can occur at any age but typically occurs in adults from the fourth to sixth decade and in children prior to the age of 4 years. Females and males are affected equally and there does not appear to be any racial or geographical predilection.
What is the Cause of the Disease?
The etiology of GEH is unknown. It represents a reactive proliferation of histiocytes for which the cause has not been found. There has been speculation that the non-Langerhans cell histiocytoses, especially benign cephalic histiocytosis, juvenile xanthogranuloma and GEH, are variants of the same disease process and represent a spectrum of disease. According to this theory GEH may exist as two subsets: the first a distinct, self-limiting condition and the second an early, undifferentiated stage of other histiocytic disorders. Some have postulated that GEH may represent a reaction to an infectious process, and reports exist of GEH occurring in association with rheumatic fever and following roseola infantum.
There have been two reports of GEH occurring in association with underlying acute myeloid leukemia. In one case, the malignancy and the skin eruption presented simultaneously while in the other the skin eruption preceded the malignancy by 18 months. The significance of this association remains unclear and, as a rule, GEH is not thought to represent a paraneoplastic phenomenon.
Systemic Implications and Complications
For the most part GEH is a benign, self-resolving non-Langerhans histiocytosis that is not associated with any systemic complications or other disease processes. However, speculation exists regarding whether GEH may represent an early, undifferentiated stage of other histiocytic disorders. A case of GEH evolving into xanthoma disseminatum in a 4-year-old boy supports this theory and illustrates the necessity of long-term follow-up of GEH patients with repeated biopsies and histopathologic analysis of any changing lesions.
There are no clinical, histologic or laboratory investigations that can predict a patient’s course of disease, so close clinical follow-up is warranted. While two cases of GEH occurring in association with acute myeloid leukemia exist, the association between these two entities remains unclear, and it is not recommended to routinely screen for malignancy in patients presenting with GEH. Age-appropriate cancer screening and a work-up of any abnormalities noted on history or physical examination is sufficient.
Table III. Treatment Options for Generalized Eruptive Histiocytoma
|No topical therapies have been described for the treatment of GEH1) Isotretinoin 10 to 40mg orally daily2) Hydroxychloroquine sulphate 200mg orally BID3) Prednisone 40mg orally daily tapered by 5mg every 2 weeks until at 20mg OR IV hydrocortisone 400mg daily on week 1 and 300mg daily on week 24)Thalidomide 100mg PO daily|
Surgical excision of individual lesions
Optimal Therapeutic Approach for this Disease
Given that the lesions of GEH are asymptomatic and resolve spontaneously without further sequelae, treatment is not necessary. However, the multiple lesions commonly occurring on the face can greatly impact patients’ appearance and self-esteem and in many cases therapy is warranted. Given the rarity of the condition, there is little evidence in the literature for any treatments for GEH, and only a few case reports exist outlining possible treatment options.
Physical modalities such as cryotherapy are generally well tolerated and have been described as effective in two case reports; however, larger nodular lesions have proven more resistant to treatment. Though it would be difficult to treat all lesions in a single visit with this modality, the most bothersome lesions can be selected by the patient and treated. Cryotherapy is a non-invasive and easily administered treatment option for GEH with few serious side effects.
No topical therapies have been described in the treatment of GEH, and given the extent of the eruption and number of lesions involved, they would likely be difficult to adequately apply.
Isotretinoin has demonstrated success in the treatment of Langerhans cell histiocytoses as well as sinus histiocytosis with massive lymphadenopathy. A single case of isotretinoin as treatment for GEH proved successful with resolution of most lesions and lack of appearance of new lesions; however, the patient chose to discontinue treatment after 8 months, and the long-term utility of isotretinoin in GEH is unknown.
A single case of combined therapy with hydroxychloroquine sulphate, IV hydrocortisone followed by oral prednisone and thalidomide on a 5-month tapered dosing schedule led to resolution of lesions without recurrence in one patient. While this combination of treatments proved successful, there is a high potential for serious side effects and given that GEH tends to self-resolve, the risks versus benefits of these medications must be weighed in each case prior to starting this regimen. No reports exist regarding whether any of the medications in this regimen would be effective individually.
Surgical excision of the lesions of GEH is not recommended as there are typically hundreds of lesions, making excision of all of them impossible. Also, lesions eventually resolve without residual scarring and surgical excision leaves a visible scar. Individual lesions that are extremely bothersome to the patient or interfering with basic functions like vision can be considered for surgical excision.
GEH is diagnosed based on history and physical examination demonstrating features of the disease and the fitting histopathologic and immunohistochemical findings. Once a diagnosis of GEH is established, patients must be reassured regarding the benign nature of this condition. New crops of lesions may continue to appear for years, however, lesions eventually self-resolve with complete disappearance or more rarely with residual brown macules. As such, treatment is not necessary and not warranted unless the patient is interested. In patients who wish to undergo treatment, the risks must be discussed in detail and it is recommended that the least invasive treatment measures such as cryotherapy be the first line. Given its benign and asymptomatic nature and self-resolving course, it is not recommended that treatment be considered for children with GEH.
Throughout the course of disease, patients should be routinely followed for a full functional review and skin examination to track the appearance and disappearance of lesions and to ensure that lesions have not changed in any way. Any suspicious-appearing lesions should be biopsied to rule out progression of disease to another non-Langerhans cell histiocytosis. Patients should be screened for any other changes in their health and appropriate investigations arranged for any new symptoms since GEH has rarely been associated with malignancy, namely acute myeloid leukemia.
Unusual Clinical Scenarios to Consider in Patient Management
GEH has been reported to occur simultaneously with rheumatic fever and following roseola infantum so patients presenting with GEH, especially in the pediatric population, should be questioned regarding any infectious symptoms during or just prior to the onset of their eruption. In both of these cases, lesions of GEH resolved within 8 months of presentation.
GEH has also evolved into another more severe non-Langerhans cell histiocytosis, xanthoma disseminatum. As such, patients must be monitored to rule out any changes in their condition suggestive of a new disorder such as new onset or worsening of mucous membrane involvement, or increasingly xanthomatous skin lesions clustering into plaques. Since rare reports of GEH occurring simultaneously with acute myeloid leukemia, it is also advised to conduct a functional review at each visit to rule out underlying systemic symptoms suggestive of malignancy. If any symptoms are present, a workup for acute myeloid leukemia including complete blood count with differential and blood smear should be undertaken.
Treatment options for GEH are limited by a lack of evidence, thus therapeutic options should be weighed by both the physician and patient and patients should understand the relatively experimental nature and lack of evidence for therapeutics prior to undergoing treatment.
What is the Evidence?
Deng, YJ, Hao, F, Zhou, CL, Sun, RS, Xiang, MM, Wang, JW. “Generalized eruptive histiocytosis: a possible therapeutic cure?”. Br J Dermatol. vol. 150. 2004. pp. 155-77. (This article describes the case of a 39-year-old man with GEH for 12 years that was successfully treated with oral hydroxycholorquine, thalidomide and IV hydrocortisone followed by oral prednisone. The article outlines the possible pathophysiologic mechanisms contributing to the success of these medications in treating GEH.)
Klemke, CD, Dippel, E, Geilen, CC, Koenigsmann, MP, Thiel, E, Orfanos, CE. “Atypical generalized eruptive histiocytosis associated with acute monocytic leukemia”. J Am Acad Dermatol. vol. 49. 2003. pp. 233-6. (This article describes the case of a 59-year-old man with a 7-month history of GEH who was diagnosed with acute monocytic leukemia on bone marrow biopsy. The article outlines the differential diagnosis of this patient's presentation and stresses the importance of malignancy screening in patients presenting with GEH.)
Kwinter, J, DeKoven, J. “Generalized eruptive histiocytoma treated with isotretinoin”. J Cutan Med Surg. vol. 13. 2009. pp. 146-50. (This article describes the case of a 53-year-old female with GEH who was successfully treated with isotretinoin. The first report of isotretinoin as treatment for GEH the article also outlines the clinical and histopathologic differences between the non-Langerhans cell histiocytoses.)
Matsushima, Y, Ohnishi, K, Ishikawa, O. “Generalized eruptive histiocytoma of childhood associated wtih rheumatic fever”. Eur J Dermatol. vol. 9. 1999. pp. 548-50. (This article describes GEH diagnosed in a five-year-old girl with concurrent rheumatic fever. The article describes the clinical, histopathologic and electron microscopic findings of GEH.)
Repiso, T, Roca-Miralles, M, Kanitakis, J, Castells-Rodellas, A. “Generalized eruptive histiocytoma evolving into xanthoma disseminatum in a 4-year-old boy”. Br J Dermatol. vol. 132. 1995. pp. 978-82. (This article describes the case of a 4-year-old boy who developed lesions clinically and histopathologically consistent with GEH over the course of 8 months. The lesions subsequently changed and were eventually clinically and histopathologicallly in keeping with xanthoma disseminatum, with the child also developing diabetes insipidus. The article explores the concept that GEH and xanthoma disseminatum are variants of histiocytic disorders that all lie along a spectrum of disease.)
Seward, JL, Malone, JC, Callen, JP. “Generalized eruptive histiocytosis”. J Am Acad Dermatol. vol. 50. 2004. pp. 116-20. (This article describes the case of a middle-aged man with GEH and describes the clinical, histopathologic and electron microscopic findings of GEH. It chronicles all reported cases of GEH up to 2004 and differentiates between all the non-Langerhans cell histocytoses.)
Statham, BN, Farris, GM, Cotterill, JA. “Atypical eruptive histiocytosis—a marker of underlying malignancy?”. Br J Dermatol. vol. 110. 1984. pp. 103-5. (This article describes the case of a man presenting with GEH as the initial presentation of acute myelomonocytic leukemia. The article outlines the clinical differential diagnosis of GEH and outlines the importance of malignancy screening in GEH patients.)
Tamiya, H, Tsuruta, D, Takeda, E, Moriwaki, K, Kobayash, H, Ishii, M. “Generalized eruptive histiocytoma with rapid progression and resolution following exanthema subitum”. Clin Exp Dermatol. vol. 30. 2005. pp. 294-307. (This article describes the case of a 14-month-old female who was diagnosed with exanthema subitum (roseola infantum), and 2 weeks following resolution of her infectious symptoms developed cutaneous lesions clinically and histologically compatible with GEH. The lesions resolved 1 month following presentation.)
Zelger, B, Burgdorf, WHC. “The cutaneous "histiocytoses."”. Adv Dermatol. vol. 17. 2001. pp. 77-114. (Provides a comprehensive overview of the non-Langerhans cell histiocytoses.)
Verma, SB. “Generalized eruptive histiocytomas and juvenile eruptive xanthogranolomas in a 10-year-old boy: a potpourri of exotic terms indicating the need for unification”. International Journal of Dermatology.. vol. 51. 2012. pp. 445-44. (This article describes the case of a 10 year old male with lesions of both generalized eruptive histiocytoma and eruptive juvenile xanthogranulomas. These two conditions have not been reported simultaneously previously, and supports the theory that the histiocytoses may represent a continuous spectrum of disease)
FernandaCardoso, NBS, Lupi, O. “Generalized eruptive histiocytoma: a rare disease in an elderly patient”. Anais brasileiros de dermatologia.. vol. 88. 2013. pp. 105-108. (A case report describing generalized eruptive histiocytoma in a 79 year old male. There are very few reported cases GEH in elderly individuals, so this case highlights a new patient population affected by this condition.)
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- Are You Confident of the Diagnosis?
- Who is at Risk for Developing this Disease?
- What is the Cause of the Disease?
- Systemic Implications and Complications
- Treatment Options
- Optimal Therapeutic Approach for this Disease
- Patient Management
- Unusual Clinical Scenarios to Consider in Patient Management
- What is the Evidence?