A 23-year-old-man of Mexican descent presented in July of 2013 with an extensive papular eruption on his bilateral lower extremities. The papules ranged in size from 0.2 to 1.0 cm, both firm and soft, without scale or crust and were distributed symmetrically. The lesions were overlying a confluent, red-brown, smooth, erythematous skin with a serpiginous border extending from mid-calf up to his thighs, with trace pitting edema (Figures 1A-C).
Over the next several months, the papules spread from his posterior calvesup to his inguinal folds, increasing in size and number. He had no systemic signs or symptoms. The only medication that the patient took during this time was clonazepam, for a new diagnosis of anxiety. He did not try any topical or oral medications for the skin lesions. Besides anxiety, the patient also had a history of stress-induced urticaria. He had no family history of skin diseases. A limited battery of laboratory tests were performed in Mexico, revealing a complete blood count within normal limits, a metabolic panel showing hypoalbuminemia and a normal lipid profile. Viral serologies and an autoimmune workup were not performed. Imaging studies were within normal limits.
Biopsies of the patient’s lesions procured at different time points in the patient’s clinical course demonstrated an extensive dermal histiocytic infiltrate, accompanied by concomitant interstitial mucin deposition (Figures 2A-B). The histiocytoid cells 
ranged from being rounded and epithelioid to exhibiting a somewhat spindled appearance, especially at the base of the infiltrate. The cell nuclei were reniform and irregularly contoured in shape, with somewhat thickened nuclear membranes. There was a moderate degree of pleomorphism to the cell population, with some cells being quite large (50-100 µm), although the majority of the cells were monotypic, in the 12 to 15 µm size range (Figures 2C1-2). The cells had vesicular nuclei with multiple chromocenters and abundant eosinophilic to basophilic cytoplasm. The pleomorphism was less conspicuous at the base of the lesions. No significant mitotic activity was identified. Although the dominant histiocytic infiltrate was mononuclear, a few multinucleated cells were noted. There were many admixed neutrophils and plasma cells in the infiltrate, although without emperilopolesis by the larger histiocytic elements (Figure 3).
An extensive array of immunohistochemical stains were performed. The mucin deposition in the dermis was highlighted by an Alcian blue preparation. CD11c and CD14 stains highlighted the infiltrate (Figures 3 and 4). A CD1a preparation showed positivity amidst reactive Langerhans cells (LCs). There was extensive immunoreactivity of the histiocytes for CD43 and CD68 with a considerable degree of positivity amidst the deeper-seated, dendritic spindled elements. A myeloperoxidase preparation was positive amidst neutrophils, while the majority of the histiocytes were essentially negative. A CD79A highlighted reactive plasma cells. There was extensive staining throughout the infiltrate for factor XIIIa (Figure 5) and CD34. The staining intensity was quite varied ranging from being weakly to strongly positive. An S100 preparation showed positivity amidst a few of the larger elements noted superficially, while most of the infiltrate was negative. Significant immunoreactivity was not identified for CD30 or a pan-cytokeratin. Similarly, a Langerin stain was negative. There was also rather striking immunoreactivity of the infiltrate for CD34.
Discussion
The histiocytopathy syndromes are proliferative disorders of monocytes exhibiting varied terminal differentiation ranging from infiltrates of scavenger macrophage origin to a monocyte with dendritic cell (DC) properties. The macrophage has as its main function phagocytosis, while the DCs are further subcategorized according to their location in tissue and inherent antigen presenting properties.
DCs provide an essential link between innate and adaptive immunity by virtue of their antigen-presenting activity and cytokine production. The DCs can largely be divided into 3 subsets represented by the LCs, myeloid DCs (mDCs) and the plasmacytoid DCs (pDCs), respectively. The latter 2 DCs have also been designated DC1 and DC2, respectively. The mDCs exist in 3 main compartments: peripheral tissue DCs, secondary lymphoid organ resident DCs and circulating blood DCs. In the skin, the peripheral tissue DCs fall under the designation of dermal dendrocytes. Given a common CD34 positive stem cell origin for both LCs and mDCs, it is not surprising that the mDCs can differentiate into LCs.
The mDCs are characterized by the production of a large number of soluble factors including interleukin (IL)-6, IL-8, IL-10, IL-12, and the expression of toll-like receptors (TLR) 2, 4 and 7. A critical function of the mDCs is to prime T cells to help naïve B cells to produce large amounts of IgM and switch isotypes toward IgG and IgA. In contrast, LCs are not capable of regulating B cell differentiation; mDCs typically express a myeloid marker profile. In this regard, they are CD11c+ and lysozyme positive and show variable positivity for CD163 and CD68. They are typically myeloperoxidase negative.
In addition, more terminally differentiated myeloid markers such as CD14, CD83 and HLA-DR can be observed. The mDC is a somewhat malleable cell that can differentiate further to exhibit an overlapping phenotypic profile with the pDCs such as myxovirus resistance protein A (MxA), CD56 and CD123; as a result of this overlapping phenotypic profile these cells fall under the designation of an interferon dendritic cell (IF-DC). The resident dermal DCs is typically factor XIIIa positive and does not have any overlapping phenotypic features with a pDC and hence is not considered an IF-DC. The exact role of the peripheral blood mDCs is unclear; however, in human blood, the majority of the mDCs express BDCA-1 while a minor subset express BDCA-3. The third subset express neither BDCA-1 nor BDCA-3, although exhibit positivity for CD16.
In contrast, pDCs are characterized by their plasma cell-like morphology based primarily on the eccentric disposition of the nucleus, production of large amounts of type I interferons and expression of TLRs 7 and 9. They can express CD2 and CD7 along with MxA, an IF-alpha inducible protein and TCL1 oncogene; pDCs are characterized by their expression of CD123, although CD123 is not specific for pDCs. CD123, the IL-3 receptor, is found on various pluripotent hematopoietic precursor cells promoting specific lines of differentiation. One of the most specific antigens expressed by pDCs is CD303 (BDCDA2). Like the mDCs, they too may also express CD83, a cell surface molecule expressed by mature DCs. It should be noted that the exact lineage affiliation of pDCs remains undefined, although a lymphoid precursor seems likely. However, they are distinct from mDCs; they do not express myeloid specific markers such as lysozyme, myeloperoxidase and CD11c. They are BDCA-2 positive. Their main role is one related to enhancement of innate immunity through the elaboration of IF-alpha; pDCs are not involved in antigen processing.
Cutaneous clonal monocyte proliferations are derived from these aforesaid cell types and accordingly have been categorized into 3 classes based on the nature of the proliferating cell: Class I (LC histiocytosis), Class II (macrophage/dermal dendrocyte related histiocytoses) and Class III (malignant histiocytosis).1
Article continues on page 2
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In this case, histiocytes had a very distinctive phenotypic profile, whereby they were terminally differentiated CD14-positive monocytes that also showed immunoreactivity for CD68, CD11c and factor XIIIa, without positivity for CD83 and myeloperoxidase. A minor component of the histiocytic infiltrate, namely the somewhat pleomorphic multinucleated cell were S100 positive, although without any concomitant immunoreactivity of Langerin and CD1A. The CD34 preparation was difficult to interpret because of the extensive staining of the reticulin network and blood vessels. Overall, the phenotypic profile was compatible with a form of histiocytosis composed of resident dermal DC derivation.2
The factor XIIIa-positive, dermal dendritic histiocytopathies are defined by juvenile xanthogranuloma, xanthoma disseminatum, Rosai-Dorfman disease, generalized eruptive histiocytosis (GEH) and Erdheim-Chester disease. 3-5 The pleomorphism present amidst the histiocytes is quite characteristic for all factor XIIIa dermal dendritic histiocytopathies, and especially for juvenile xanthogranuloma and Rosai-Dorfman disease.3,5,6 In addition, the presence of other inflammatory cell elements, including plasma cells and neutrophils, is also an intrinsic feature of these diseases.3,5-7 There is considerable clinical and histopathologic overlap between these entities.
Another important differential diagnosis, which is not a Factor XIIIA-positive, dermal dendritic histiocytopathy, is histiocytic sarcoma. Histiocytic sarcoma is an extremely rare, malignant neoplasm exhibiting morphologic and immunophenotypic evidence of histiocytic differentiation. It is diagnosed on the basis of highly atypical morphology of tumor cells and expression of histiocyte-associated markers. Although the infiltrate in this case did have a moderately atypical morphology and did express histiocytic markers, the clinical presentation and regression of the lesions aid in the exclusion of the diagnosis of histiocytic sarcoma.8 All in all, the primarily monotypic histiocytic infiltrate, the immunohistochemical profile, the lack of staining for LC markers, the absence of xanthomatous cells and the clinical presentation including the regressive tendency of the lesions were most compatible with a diagnosis of GEH.7
GEH is a rare type of factor XIIIa-positive histiocytopathy, characterized by symmetric distribution of red-brown papules on the trunk, proximal extremities and face. The lesions tend to regress spontaneously, leaving behind hyperpigmented macules, a finding well exemplified by this case. It is primarily a disease of adults.9,10
GEH is an extremely rare, benign, non-LC histiocytosis, which was first described in 1963 by Wikelmann and Müller, amidst 3 adult patients.11 There have been a few cases described in children and overall, less than 50 cases have been reported worldwide. The onset of this disease in adults is typically in third to sixth decades of life; while in children, the commencement is before the age 4. GEH manifests in red to brown papules, typically less than 1.0 cm, distributed on the trunk, proximal extremities and occasionally, the face. The papules usually have a striking symmetrical disposition and rarely involve mucosal surfaces or viscera. Within several months, the lesions resolve, leaving behind hyperpigmented macules.1,11,12 The etiology of the condition is unknown but likely reflects a clonal disorder of myelomonocytic cells. It is unclear if GEH has the same association with underlying myeloproliferative disease as conditions such as histiocytosis X.7,13,14 Diagnosis is made based on histopathologic and immunohistochemical examination. We present a case of GEH in a 23-year-old man, with detailed focus on the clinical presentation and histopathology, in order to improve understanding of the diagnosis of this disease.
Recent medical literature has suggested that GEH may be divided into 2 subsets: an early, indifferent stage of other histiocytic disorders and a specific condition without a subsequent disorder.1,9 GEH is generally not associated with malignancy and the characteristic regression has been postulated to be mediated by massive apoptotic cell death.15 As there are no clinical or histologic parameters that may predict a patient’s development of other, more severe forms of histiocytosis, close follow-up is essential.9 We noted the the symmetrical nature of the eruption both in the context of the papular component and erthrodermic element. In reviewing the literature, it would suggest that the appearance manifested by this case is typical for this disorder recognizing that typical is an oxymoron in the context of a condition that is so rare. Other forms of histiocytopathy do not have this distinctive pattern of papular erythroderma.
This article presents an exceptionally rare but classic presentation of GEH based on a careful integration of the clinical features, light microscopic findings and phenotypic profile.
Dr. Magro is the director of dermatopathology at Weill Cornell Medicine in New York, NY.
Dr. Kazi is a dermatology resident at Columbia Medical Center in New York, NY.
Dr. Bernert is a dermatopathologist at Arizona Dermatopathology (Aurora Diagnostics) in Scottsdale, AZ.
Dr. Moussa is a physician at LECOM/Alta Dermatology in Scottsdale, AZ.
Disclosure: The authors report no relevant financial relationships.
References
1. Cardoso F, Serafini NB, Reis BD, Nuñez MD, Nery JA, Lupi O. Generalized eruptive histiocytoma: a rare disease in an elderly patient. An Bras Dermatol. 2013;88(1):105-108.
2. Santegoets SJ, Gibbs S, Kroeze K, et al. Transcriptional profiling of human skin-resident Langerhans cells and CD1a+ dermal dendritic cells: differential states suggest distinct functions. J Leukoc Biol. 2008;84(1):143-151.
3. Verma SB. Generalized eruptive histiocytomas and juvenile eruptive xanthogranulomas in a 10-year-old boy: a potpourri of exotic terms indicating the need for unification. Int J Dermatol. 2012;51(4):445-447.
4. Purgina B, Jaffe R, Monaco SE, et al. Cytomorphology of Erdheim-Chester disease presenting as a retroperitoneal soft tissue lesion. Cyto J. 2011;8:22.
5. Perrin C, Michiels JF, Lacour JP, Chagnon A, Fuzibet JG. Sinus histiocytosis (Rosai-Dorfman disease) clinically limited to the skin: an immunohistochemical and ultrastructural study. J Cutan Pathol. 1993;20(4):368-374.
6. Singh NG, Mannan AA. Cutaneous Rosai-Dorfman disease: report of a case. Indian J Pathol Microbiol. 2013;56(1):60-61.
7. Sagransky M, Deng AC, Magro CM. Primary cutaneous Langerhans cell sarcoma: a report of four cases and review of the literature. Am J Dermatopathol. 2013;35(2):196-204.
8.Takahashi E, Nakamura S, Histiocytic sarcoma: an updated literature review based on the 2008 WHO classification. J Clin Exp Hematop. 2013;53(1):1-8.
9. Fernández-Jorge B, Goday-Buján J, Del Pozo Losada J, Alvarez-Rodriguez R, Fonseca E. A case of generalized eruptive histiocytosis. Acta Derm Venereol. 2007;87(6):533-536.
10. Wee SH, Kim HS, Chang SN, Kim DK, Park WH. Generalized eruptive histiocytoma: a pediatric case. Pediatr Dermatol. 2000;17(6):453-455.
11. Winkelmann RK, Muller SA. Generalized eruptive histiocytoma: a benign papular histiocytic reticulosis. Arch Dermatol. 1963;88:586-596.
12. Lan Ma H, Metze D, Luger TA, Steinhoff M. Successful treatment of generalized eruptive histiocytoma with PUVA. J Dtsch Dermatol Ges. 2007;5(2):131-134.
13. Klemke CD, Dippel E, Geilen CC, et al. Atypical generalized eruptive histiocytosis associated with acute monocytic leukemia. J Am Acad Dermatol. 2003;49(5 suppl):S233-S236.
14. Montero I, Gutiérrez-González R, Ginarte M, Toribio J. Generalized eruptive histiocytosis in a patient with chronic myelomonocytic leukemia. Actas Dermosifiliogr. 2012;103(7):643-644.
15. Tang X, Shen H, Xu A, et al. Spontaneous regression of generalized eruptive histiocytosis: possible involvement of apoptosis? Int J Dermatol. 2007;46(10):1073-1075.
A 23-year-old-man of Mexican descent presented in July of 2013 with an extensive papular eruption on his bilateral lower extremities. The papules ranged in size from 0.2 to 1.0 cm, both firm and soft, without scale or crust and were distributed symmetrically. The lesions were overlying a confluent, red-brown, smooth, erythematous skin with a serpiginous border extending from mid-calf up to his thighs, with trace pitting edema (Figures 1A-C).
Over the next several months, the papules spread from his posterior calvesup to his inguinal folds, increasing in size and number. He had no systemic signs or symptoms. The only medication that the patient took during this time was clonazepam, for a new diagnosis of anxiety. He did not try any topical or oral medications for the skin lesions. Besides anxiety, the patient also had a history of stress-induced urticaria. He had no family history of skin diseases. A limited battery of laboratory tests were performed in Mexico, revealing a complete blood count within normal limits, a metabolic panel showing hypoalbuminemia and a normal lipid profile. Viral serologies and an autoimmune workup were not performed. Imaging studies were within normal limits.
Biopsies of the patient’s lesions procured at different time points in the patient’s clinical course demonstrated an extensive dermal histiocytic infiltrate, accompanied by concomitant interstitial mucin deposition (Figures 2A-B). The histiocytoid cells 
ranged from being rounded and epithelioid to exhibiting a somewhat spindled appearance, especially at the base of the infiltrate. The cell nuclei were reniform and irregularly contoured in shape, with somewhat thickened nuclear membranes. There was a moderate degree of pleomorphism to the cell population, with some cells being quite large (50-100 µm), although the majority of the cells were monotypic, in the 12 to 15 µm size range (Figures 2C1-2). The cells had vesicular nuclei with multiple chromocenters and abundant eosinophilic to basophilic cytoplasm. The pleomorphism was less conspicuous at the base of the lesions. No significant mitotic activity was identified. Although the dominant histiocytic infiltrate was mononuclear, a few multinucleated cells were noted. There were many admixed neutrophils and plasma cells in the infiltrate, although without emperilopolesis by the larger histiocytic elements (Figure 3).
An extensive array of immunohistochemical stains were performed. The mucin deposition in the dermis was highlighted by an Alcian blue preparation. CD11c and CD14 stains highlighted the infiltrate (Figures 3 and 4). A CD1a preparation showed positivity amidst reactive Langerhans cells (LCs). There was extensive immunoreactivity of the histiocytes for CD43 and CD68 with a considerable degree of positivity amidst the deeper-seated, dendritic spindled elements. A myeloperoxidase preparation was positive amidst neutrophils, while the majority of the histiocytes were essentially negative. A CD79A highlighted reactive plasma cells. There was extensive staining throughout the infiltrate for factor XIIIa (Figure 5) and CD34. The staining intensity was quite varied ranging from being weakly to strongly positive. An S100 preparation showed positivity amidst a few of the larger elements noted superficially, while most of the infiltrate was negative. Significant immunoreactivity was not identified for CD30 or a pan-cytokeratin. Similarly, a Langerin stain was negative. There was also rather striking immunoreactivity of the infiltrate for CD34.
Discussion
The histiocytopathy syndromes are proliferative disorders of monocytes exhibiting varied terminal differentiation ranging from infiltrates of scavenger macrophage origin to a monocyte with dendritic cell (DC) properties. The macrophage has as its main function phagocytosis, while the DCs are further subcategorized according to their location in tissue and inherent antigen presenting properties.
DCs provide an essential link between innate and adaptive immunity by virtue of their antigen-presenting activity and cytokine production. The DCs can largely be divided into 3 subsets represented by the LCs, myeloid DCs (mDCs) and the plasmacytoid DCs (pDCs), respectively. The latter 2 DCs have also been designated DC1 and DC2, respectively. The mDCs exist in 3 main compartments: peripheral tissue DCs, secondary lymphoid organ resident DCs and circulating blood DCs. In the skin, the peripheral tissue DCs fall under the designation of dermal dendrocytes. Given a common CD34 positive stem cell origin for both LCs and mDCs, it is not surprising that the mDCs can differentiate into LCs.
The mDCs are characterized by the production of a large number of soluble factors including interleukin (IL)-6, IL-8, IL-10, IL-12, and the expression of toll-like receptors (TLR) 2, 4 and 7. A critical function of the mDCs is to prime T cells to help naïve B cells to produce large amounts of IgM and switch isotypes toward IgG and IgA. In contrast, LCs are not capable of regulating B cell differentiation; mDCs typically express a myeloid marker profile. In this regard, they are CD11c+ and lysozyme positive and show variable positivity for CD163 and CD68. They are typically myeloperoxidase negative.
In addition, more terminally differentiated myeloid markers such as CD14, CD83 and HLA-DR can be observed. The mDC is a somewhat malleable cell that can differentiate further to exhibit an overlapping phenotypic profile with the pDCs such as myxovirus resistance protein A (MxA), CD56 and CD123; as a result of this overlapping phenotypic profile these cells fall under the designation of an interferon dendritic cell (IF-DC). The resident dermal DCs is typically factor XIIIa positive and does not have any overlapping phenotypic features with a pDC and hence is not considered an IF-DC. The exact role of the peripheral blood mDCs is unclear; however, in human blood, the majority of the mDCs express BDCA-1 while a minor subset express BDCA-3. The third subset express neither BDCA-1 nor BDCA-3, although exhibit positivity for CD16.
In contrast, pDCs are characterized by their plasma cell-like morphology based primarily on the eccentric disposition of the nucleus, production of large amounts of type I interferons and expression of TLRs 7 and 9. They can express CD2 and CD7 along with MxA, an IF-alpha inducible protein and TCL1 oncogene; pDCs are characterized by their expression of CD123, although CD123 is not specific for pDCs. CD123, the IL-3 receptor, is found on various pluripotent hematopoietic precursor cells promoting specific lines of differentiation. One of the most specific antigens expressed by pDCs is CD303 (BDCDA2). Like the mDCs, they too may also express CD83, a cell surface molecule expressed by mature DCs. It should be noted that the exact lineage affiliation of pDCs remains undefined, although a lymphoid precursor seems likely. However, they are distinct from mDCs; they do not express myeloid specific markers such as lysozyme, myeloperoxidase and CD11c. They are BDCA-2 positive. Their main role is one related to enhancement of innate immunity through the elaboration of IF-alpha; pDCs are not involved in antigen processing.
Cutaneous clonal monocyte proliferations are derived from these aforesaid cell types and accordingly have been categorized into 3 classes based on the nature of the proliferating cell: Class I (LC histiocytosis), Class II (macrophage/dermal dendrocyte related histiocytoses) and Class III (malignant histiocytosis).1
In this case, histiocytes had a very distinctive phenotypic profile, whereby they were terminally differentiated CD14-positive monocytes that also showed immunoreactivity for CD68, CD11c and factor XIIIa, without positivity for CD83 and myeloperoxidase. A minor component of the histiocytic infiltrate, namely the somewhat pleomorphic multinucleated cell were S100 positive, although without any concomitant immunoreactivity of Langerin and CD1A. The CD34 preparation was difficult to interpret because of the extensive staining of the reticulin network and blood vessels. Overall, the phenotypic profile was compatible with a form of histiocytosis composed of resident dermal DC derivation.2
The factor XIIIa-positive, dermal dendritic histiocytopathies are defined by juvenile xanthogranuloma, xanthoma disseminatum, Rosai-Dorfman disease, generalized eruptive histiocytosis (GEH) and Erdheim-Chester disease. 3-5 The pleomorphism present amidst the histiocytes is quite characteristic for all factor XIIIa dermal dendritic histiocytopathies, and especially for juvenile xanthogranuloma and Rosai-Dorfman disease.3,5,6 In addition, the presence of other inflammatory cell elements, including plasma cells and neutrophils, is also an intrinsic feature of these diseases.3,5-7 There is considerable clinical and histopathologic overlap between these entities.
Another important differential diagnosis, which is not a Factor XIIIA-positive, dermal dendritic histiocytopathy, is histiocytic sarcoma. Histiocytic sarcoma is an extremely rare, malignant neoplasm exhibiting morphologic and immunophenotypic evidence of histiocytic differentiation. It is diagnosed on the basis of highly atypical morphology of tumor cells and expression of histiocyte-associated markers. Although the infiltrate in this case did have a moderately atypical morphology and did express histiocytic markers, the clinical presentation and regression of the lesions aid in the exclusion of the diagnosis of histiocytic sarcoma.8 All in all, the primarily monotypic histiocytic infiltrate, the immunohistochemical profile, the lack of staining for LC markers, the absence of xanthomatous cells and the clinical presentation including the regressive tendency of the lesions were most compatible with a diagnosis of GEH.7
GEH is a rare type of factor XIIIa-positive histiocytopathy, characterized by symmetric distribution of red-brown papules on the trunk, proximal extremities and face. The lesions tend to regress spontaneously, leaving behind hyperpigmented macules, a finding well exemplified by this case. It is primarily a disease of adults.9,10
GEH is an extremely rare, benign, non-LC histiocytosis, which was first described in 1963 by Wikelmann and Müller, amidst 3 adult patients.11 There have been a few cases described in children and overall, less than 50 cases have been reported worldwide. The onset of this disease in adults is typically in third to sixth decades of life; while in children, the commencement is before the age 4. GEH manifests in red to brown papules, typically less than 1.0 cm, distributed on the trunk, proximal extremities and occasionally, the face. The papules usually have a striking symmetrical disposition and rarely involve mucosal surfaces or viscera. Within several months, the lesions resolve, leaving behind hyperpigmented macules.1,11,12 The etiology of the condition is unknown but likely reflects a clonal disorder of myelomonocytic cells. It is unclear if GEH has the same association with underlying myeloproliferative disease as conditions such as histiocytosis X.7,13,14 Diagnosis is made based on histopathologic and immunohistochemical examination. We present a case of GEH in a 23-year-old man, with detailed focus on the clinical presentation and histopathology, in order to improve understanding of the diagnosis of this disease.
Recent medical literature has suggested that GEH may be divided into 2 subsets: an early, indifferent stage of other histiocytic disorders and a specific condition without a subsequent disorder.1,9 GEH is generally not associated with malignancy and the characteristic regression has been postulated to be mediated by massive apoptotic cell death.15 As there are no clinical or histologic parameters that may predict a patient’s development of other, more severe forms of histiocytosis, close follow-up is essential.9 We noted the the symmetrical nature of the eruption both in the context of the papular component and erthrodermic element. In reviewing the literature, it would suggest that the appearance manifested by this case is typical for this disorder recognizing that typical is an oxymoron in the context of a condition that is so rare. Other forms of histiocytopathy do not have this distinctive pattern of papular erythroderma.
This article presents an exceptionally rare but classic presentation of GEH based on a careful integration of the clinical features, light microscopic findings and phenotypic profile.
Dr. Magro is the director of dermatopathology at Weill Cornell Medicine in New York, NY.
Dr. Kazi is a dermatology resident at Columbia Medical Center in New York, NY.
Dr. Bernert is a dermatopathologist at Arizona Dermatopathology (Aurora Diagnostics) in Scottsdale, AZ.
Dr. Moussa is a physician at LECOM/Alta Dermatology in Scottsdale, AZ.
Disclosure: The authors report no relevant financial relationships.
References
1. Cardoso F, Serafini NB, Reis BD, Nuñez MD, Nery JA, Lupi O. Generalized eruptive histiocytoma: a rare disease in an elderly patient. An Bras Dermatol. 2013;88(1):105-108.
2. Santegoets SJ, Gibbs S, Kroeze K, et al. Transcriptional profiling of human skin-resident Langerhans cells and CD1a+ dermal dendritic cells: differential states suggest distinct functions. J Leukoc Biol. 2008;84(1):143-151.
3. Verma SB. Generalized eruptive histiocytomas and juvenile eruptive xanthogranulomas in a 10-year-old boy: a potpourri of exotic terms indicating the need for unification. Int J Dermatol. 2012;51(4):445-447.
4. Purgina B, Jaffe R, Monaco SE, et al. Cytomorphology of Erdheim-Chester disease presenting as a retroperitoneal soft tissue lesion. Cyto J. 2011;8:22.
5. Perrin C, Michiels JF, Lacour JP, Chagnon A, Fuzibet JG. Sinus histiocytosis (Rosai-Dorfman disease) clinically limited to the skin: an immunohistochemical and ultrastructural study. J Cutan Pathol. 1993;20(4):368-374.
6. Singh NG, Mannan AA. Cutaneous Rosai-Dorfman disease: report of a case. Indian J Pathol Microbiol. 2013;56(1):60-61.
7. Sagransky M, Deng AC, Magro CM. Primary cutaneous Langerhans cell sarcoma: a report of four cases and review of the literature. Am J Dermatopathol. 2013;35(2):196-204.
8.Takahashi E, Nakamura S, Histiocytic sarcoma: an updated literature review based on the 2008 WHO classification. J Clin Exp Hematop. 2013;53(1):1-8.
9. Fernández-Jorge B, Goday-Buján J, Del Pozo Losada J, Alvarez-Rodriguez R, Fonseca E. A case of generalized eruptive histiocytosis. Acta Derm Venereol. 2007;87(6):533-536.
10. Wee SH, Kim HS, Chang SN, Kim DK, Park WH. Generalized eruptive histiocytoma: a pediatric case. Pediatr Dermatol. 2000;17(6):453-455.
11. Winkelmann RK, Muller SA. Generalized eruptive histiocytoma: a benign papular histiocytic reticulosis. Arch Dermatol. 1963;88:586-596.
12. Lan Ma H, Metze D, Luger TA, Steinhoff M. Successful treatment of generalized eruptive histiocytoma with PUVA. J Dtsch Dermatol Ges. 2007;5(2):131-134.
13. Klemke CD, Dippel E, Geilen CC, et al. Atypical generalized eruptive histiocytosis associated with acute monocytic leukemia. J Am Acad Dermatol. 2003;49(5 suppl):S233-S236.
14. Montero I, Gutiérrez-González R, Ginarte M, Toribio J. Generalized eruptive histiocytosis in a patient with chronic myelomonocytic leukemia. Actas Dermosifiliogr. 2012;103(7):643-644.
15. Tang X, Shen H, Xu A, et al. Spontaneous regression of generalized eruptive histiocytosis: possible involvement of apoptosis? Int J Dermatol. 2007;46(10):1073-1075.
A 23-year-old-man of Mexican descent presented in July of 2013 with an extensive papular eruption on his bilateral lower extremities. The papules ranged in size from 0.2 to 1.0 cm, both firm and soft, without scale or crust and were distributed symmetrically. The lesions were overlying a confluent, red-brown, smooth, erythematous skin with a serpiginous border extending from mid-calf up to his thighs, with trace pitting edema (Figures 1A-C).
Over the next several months, the papules spread from his posterior calvesup to his inguinal folds, increasing in size and number. He had no systemic signs or symptoms. The only medication that the patient took during this time was clonazepam, for a new diagnosis of anxiety. He did not try any topical or oral medications for the skin lesions. Besides anxiety, the patient also had a history of stress-induced urticaria. He had no family history of skin diseases. A limited battery of laboratory tests were performed in Mexico, revealing a complete blood count within normal limits, a metabolic panel showing hypoalbuminemia and a normal lipid profile. Viral serologies and an autoimmune workup were not performed. Imaging studies were within normal limits.
Biopsies of the patient’s lesions procured at different time points in the patient’s clinical course demonstrated an extensive dermal histiocytic infiltrate, accompanied by concomitant interstitial mucin deposition (Figures 2A-B). The histiocytoid cells ranged from being rounded and epithelioid to exhibiting a somewhat spindled appearance, especially at the base of the infiltrate. The cell nuclei were reniform and irregularly contoured in shape, with somewhat thickened nuclear membranes. There was a moderate degree of pleomorphism to the cell population, with some cells being quite large (50-100 µm), although the majority of the cells were monotypic, in the 12 to 15 µm size range (Figures 2C1-2). The cells had vesicular nuclei with multiple chromocenters and abundant eosinophilic to basophilic cytoplasm. The pleomorphism was less conspicuous at the base of the lesions. No significant mitotic activity was identified. Although the dominant histiocytic infiltrate was mononuclear, a few multinucleated cells were noted. There were many admixed neutrophils and plasma cells in the infiltrate, although without emperilopolesis by the larger histiocytic elements (Figure 3).
An extensive array of immunohistochemical stains were performed. The mucin deposition in the dermis was highlighted by an Alcian blue preparation. CD11c and CD14 stains highlighted the infiltrate (Figures 3 and 4). A CD1a preparation showed positivity amidst reactive Langerhans cells (LCs). There was extensive immunoreactivity of the histiocytes for CD43 and CD68 with a considerable degree of positivity amidst the deeper-seated, dendritic spindled elements. A myeloperoxidase preparation was positive amidst neutrophils, while the majority of the histiocytes were essentially negative. A CD79A highlighted reactive plasma cells. There was extensive staining throughout the infiltrate for factor XIIIa (Figure 5) and CD34. The staining intensity was quite varied ranging from being weakly to strongly positive. An S100 preparation showed positivity amidst a few of the larger elements noted superficially, while most of the infiltrate was negative. Significant immunoreactivity was not identified for CD30 or a pan-cytokeratin. Similarly, a Langerin stain was negative. There was also rather striking immunoreactivity of the infiltrate for CD34.
Discussion
The histiocytopathy syndromes are proliferative disorders of monocytes exhibiting varied terminal differentiation ranging from infiltrates of scavenger macrophage origin to a monocyte with dendritic cell (DC) properties. The macrophage has as its main function phagocytosis, while the DCs are further subcategorized according to their location in tissue and inherent antigen presenting properties.
DCs provide an essential link between innate and adaptive immunity by virtue of their antigen-presenting activity and cytokine production. The DCs can largely be divided into 3 subsets represented by the LCs, myeloid DCs (mDCs) and the plasmacytoid DCs (pDCs), respectively. The latter 2 DCs have also been designated DC1 and DC2, respectively. The mDCs exist in 3 main compartments: peripheral tissue DCs, secondary lymphoid organ resident DCs and circulating blood DCs. In the skin, the peripheral tissue DCs fall under the designation of dermal dendrocytes. Given a common CD34 positive stem cell origin for both LCs and mDCs, it is not surprising that the mDCs can differentiate into LCs.
The mDCs are characterized by the production of a large number of soluble factors including interleukin (IL)-6, IL-8, IL-10, IL-12, and the expression of toll-like receptors (TLR) 2, 4 and 7. A critical function of the mDCs is to prime T cells to help naïve B cells to produce large amounts of IgM and switch isotypes toward IgG and IgA. In contrast, LCs are not capable of regulating B cell differentiation; mDCs typically express a myeloid marker profile. In this regard, they are CD11c+ and lysozyme positive and show variable positivity for CD163 and CD68. They are typically myeloperoxidase negative.
In addition, more terminally differentiated myeloid markers such as CD14, CD83 and HLA-DR can be observed. The mDC is a somewhat malleable cell that can differentiate further to exhibit an overlapping phenotypic profile with the pDCs such as myxovirus resistance protein A (MxA), CD56 and CD123; as a result of this overlapping phenotypic profile these cells fall under the designation of an interferon dendritic cell (IF-DC). The resident dermal DCs is typically factor XIIIa positive and does not have any overlapping phenotypic features with a pDC and hence is not considered an IF-DC. The exact role of the peripheral blood mDCs is unclear; however, in human blood, the majority of the mDCs express BDCA-1 while a minor subset express BDCA-3. The third subset express neither BDCA-1 nor BDCA-3, although exhibit positivity for CD16.
In contrast, pDCs are characterized by their plasma cell-like morphology based primarily on the eccentric disposition of the nucleus, production of large amounts of type I interferons and expression of TLRs 7 and 9. They can express CD2 and CD7 along with MxA, an IF-alpha inducible protein and TCL1 oncogene; pDCs are characterized by their expression of CD123, although CD123 is not specific for pDCs. CD123, the IL-3 receptor, is found on various pluripotent hematopoietic precursor cells promoting specific lines of differentiation. One of the most specific antigens expressed by pDCs is CD303 (BDCDA2). Like the mDCs, they too may also express CD83, a cell surface molecule expressed by mature DCs. It should be noted that the exact lineage affiliation of pDCs remains undefined, although a lymphoid precursor seems likely. However, they are distinct from mDCs; they do not express myeloid specific markers such as lysozyme, myeloperoxidase and CD11c. They are BDCA-2 positive. Their main role is one related to enhancement of innate immunity through the elaboration of IF-alpha; pDCs are not involved in antigen processing.
Cutaneous clonal monocyte proliferations are derived from these aforesaid cell types and accordingly have been categorized into 3 classes based on the nature of the proliferating cell: Class I (LC histiocytosis), Class II (macrophage/dermal dendrocyte related histiocytoses) and Class III (malignant histiocytosis).1
,
A 23-year-old-man of Mexican descent presented in July of 2013 with an extensive papular eruption on his bilateral lower extremities. The papules ranged in size from 0.2 to 1.0 cm, both firm and soft, without scale or crust and were distributed symmetrically. The lesions were overlying a confluent, red-brown, smooth, erythematous skin with a serpiginous border extending from mid-calf up to his thighs, with trace pitting edema (Figures 1A-C).
Over the next several months, the papules spread from his posterior calvesup to his inguinal folds, increasing in size and number. He had no systemic signs or symptoms. The only medication that the patient took during this time was clonazepam, for a new diagnosis of anxiety. He did not try any topical or oral medications for the skin lesions. Besides anxiety, the patient also had a history of stress-induced urticaria. He had no family history of skin diseases. A limited battery of laboratory tests were performed in Mexico, revealing a complete blood count within normal limits, a metabolic panel showing hypoalbuminemia and a normal lipid profile. Viral serologies and an autoimmune workup were not performed. Imaging studies were within normal limits.
Biopsies of the patient’s lesions procured at different time points in the patient’s clinical course demonstrated an extensive dermal histiocytic infiltrate, accompanied by concomitant interstitial mucin deposition (Figures 2A-B). The histiocytoid cells ranged from being rounded and epithelioid to exhibiting a somewhat spindled appearance, especially at the base of the infiltrate. The cell nuclei were reniform and irregularly contoured in shape, with somewhat thickened nuclear membranes. There was a moderate degree of pleomorphism to the cell population, with some cells being quite large (50-100 µm), although the majority of the cells were monotypic, in the 12 to 15 µm size range (Figures 2C1-2). The cells had vesicular nuclei with multiple chromocenters and abundant eosinophilic to basophilic cytoplasm. The pleomorphism was less conspicuous at the base of the lesions. No significant mitotic activity was identified. Although the dominant histiocytic infiltrate was mononuclear, a few multinucleated cells were noted. There were many admixed neutrophils and plasma cells in the infiltrate, although without emperilopolesis by the larger histiocytic elements (Figure 3).
An extensive array of immunohistochemical stains were performed. The mucin deposition in the dermis was highlighted by an Alcian blue preparation. CD11c and CD14 stains highlighted the infiltrate (Figures 3 and 4). A CD1a preparation showed positivity amidst reactive Langerhans cells (LCs). There was extensive immunoreactivity of the histiocytes for CD43 and CD68 with a considerable degree of positivity amidst the deeper-seated, dendritic spindled elements. A myeloperoxidase preparation was positive amidst neutrophils, while the majority of the histiocytes were essentially negative. A CD79A highlighted reactive plasma cells. There was extensive staining throughout the infiltrate for factor XIIIa (Figure 5) and CD34. The staining intensity was quite varied ranging from being weakly to strongly positive. An S100 preparation showed positivity amidst a few of the larger elements noted superficially, while most of the infiltrate was negative. Significant immunoreactivity was not identified for CD30 or a pan-cytokeratin. Similarly, a Langerin stain was negative. There was also rather striking immunoreactivity of the infiltrate for CD34.
Discussion
The histiocytopathy syndromes are proliferative disorders of monocytes exhibiting varied terminal differentiation ranging from infiltrates of scavenger macrophage origin to a monocyte with dendritic cell (DC) properties. The macrophage has as its main function phagocytosis, while the DCs are further subcategorized according to their location in tissue and inherent antigen presenting properties.
DCs provide an essential link between innate and adaptive immunity by virtue of their antigen-presenting activity and cytokine production. The DCs can largely be divided into 3 subsets represented by the LCs, myeloid DCs (mDCs) and the plasmacytoid DCs (pDCs), respectively. The latter 2 DCs have also been designated DC1 and DC2, respectively. The mDCs exist in 3 main compartments: peripheral tissue DCs, secondary lymphoid organ resident DCs and circulating blood DCs. In the skin, the peripheral tissue DCs fall under the designation of dermal dendrocytes. Given a common CD34 positive stem cell origin for both LCs and mDCs, it is not surprising that the mDCs can differentiate into LCs.
The mDCs are characterized by the production of a large number of soluble factors including interleukin (IL)-6, IL-8, IL-10, IL-12, and the expression of toll-like receptors (TLR) 2, 4 and 7. A critical function of the mDCs is to prime T cells to help naïve B cells to produce large amounts of IgM and switch isotypes toward IgG and IgA. In contrast, LCs are not capable of regulating B cell differentiation; mDCs typically express a myeloid marker profile. In this regard, they are CD11c+ and lysozyme positive and show variable positivity for CD163 and CD68. They are typically myeloperoxidase negative.
In addition, more terminally differentiated myeloid markers such as CD14, CD83 and HLA-DR can be observed. The mDC is a somewhat malleable cell that can differentiate further to exhibit an overlapping phenotypic profile with the pDCs such as myxovirus resistance protein A (MxA), CD56 and CD123; as a result of this overlapping phenotypic profile these cells fall under the designation of an interferon dendritic cell (IF-DC). The resident dermal DCs is typically factor XIIIa positive and does not have any overlapping phenotypic features with a pDC and hence is not considered an IF-DC. The exact role of the peripheral blood mDCs is unclear; however, in human blood, the majority of the mDCs express BDCA-1 while a minor subset express BDCA-3. The third subset express neither BDCA-1 nor BDCA-3, although exhibit positivity for CD16.
In contrast, pDCs are characterized by their plasma cell-like morphology based primarily on the eccentric disposition of the nucleus, production of large amounts of type I interferons and expression of TLRs 7 and 9. They can express CD2 and CD7 along with MxA, an IF-alpha inducible protein and TCL1 oncogene; pDCs are characterized by their expression of CD123, although CD123 is not specific for pDCs. CD123, the IL-3 receptor, is found on various pluripotent hematopoietic precursor cells promoting specific lines of differentiation. One of the most specific antigens expressed by pDCs is CD303 (BDCDA2). Like the mDCs, they too may also express CD83, a cell surface molecule expressed by mature DCs. It should be noted that the exact lineage affiliation of pDCs remains undefined, although a lymphoid precursor seems likely. However, they are distinct from mDCs; they do not express myeloid specific markers such as lysozyme, myeloperoxidase and CD11c. They are BDCA-2 positive. Their main role is one related to enhancement of innate immunity through the elaboration of IF-alpha; pDCs are not involved in antigen processing.
Cutaneous clonal monocyte proliferations are derived from these aforesaid cell types and accordingly have been categorized into 3 classes based on the nature of the proliferating cell: Class I (LC histiocytosis), Class II (macrophage/dermal dendrocyte related histiocytoses) and Class III (malignant histiocytosis).1
Article continues on page 2
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In this case, histiocytes had a very distinctive phenotypic profile, whereby they were terminally differentiated CD14-positive monocytes that also showed immunoreactivity for CD68, CD11c and factor XIIIa, without positivity for CD83 and myeloperoxidase. A minor component of the histiocytic infiltrate, namely the somewhat pleomorphic multinucleated cell were S100 positive, although without any concomitant immunoreactivity of Langerin and CD1A. The CD34 preparation was difficult to interpret because of the extensive staining of the reticulin network and blood vessels. Overall, the phenotypic profile was compatible with a form of histiocytosis composed of resident dermal DC derivation.2
The factor XIIIa-positive, dermal dendritic histiocytopathies are defined by juvenile xanthogranuloma, xanthoma disseminatum, Rosai-Dorfman disease, generalized eruptive histiocytosis (GEH) and Erdheim-Chester disease. 3-5 The pleomorphism present amidst the histiocytes is quite characteristic for all factor XIIIa dermal dendritic histiocytopathies, and especially for juvenile xanthogranuloma and Rosai-Dorfman disease.3,5,6 In addition, the presence of other inflammatory cell elements, including plasma cells and neutrophils, is also an intrinsic feature of these diseases.3,5-7 There is considerable clinical and histopathologic overlap between these entities.
Another important differential diagnosis, which is not a Factor XIIIA-positive, dermal dendritic histiocytopathy, is histiocytic sarcoma. Histiocytic sarcoma is an extremely rare, malignant neoplasm exhibiting morphologic and immunophenotypic evidence of histiocytic differentiation. It is diagnosed on the basis of highly atypical morphology of tumor cells and expression of histiocyte-associated markers. Although the infiltrate in this case did have a moderately atypical morphology and did express histiocytic markers, the clinical presentation and regression of the lesions aid in the exclusion of the diagnosis of histiocytic sarcoma.8 All in all, the primarily monotypic histiocytic infiltrate, the immunohistochemical profile, the lack of staining for LC markers, the absence of xanthomatous cells and the clinical presentation including the regressive tendency of the lesions were most compatible with a diagnosis of GEH.7
GEH is a rare type of factor XIIIa-positive histiocytopathy, characterized by symmetric distribution of red-brown papules on the trunk, proximal extremities and face. The lesions tend to regress spontaneously, leaving behind hyperpigmented macules, a finding well exemplified by this case. It is primarily a disease of adults.9,10
GEH is an extremely rare, benign, non-LC histiocytosis, which was first described in 1963 by Wikelmann and Müller, amidst 3 adult patients.11 There have been a few cases described in children and overall, less than 50 cases have been reported worldwide. The onset of this disease in adults is typically in third to sixth decades of life; while in children, the commencement is before the age 4. GEH manifests in red to brown papules, typically less than 1.0 cm, distributed on the trunk, proximal extremities and occasionally, the face. The papules usually have a striking symmetrical disposition and rarely involve mucosal surfaces or viscera. Within several months, the lesions resolve, leaving behind hyperpigmented macules.1,11,12 The etiology of the condition is unknown but likely reflects a clonal disorder of myelomonocytic cells. It is unclear if GEH has the same association with underlying myeloproliferative disease as conditions such as histiocytosis X.7,13,14 Diagnosis is made based on histopathologic and immunohistochemical examination. We present a case of GEH in a 23-year-old man, with detailed focus on the clinical presentation and histopathology, in order to improve understanding of the diagnosis of this disease.
Recent medical literature has suggested that GEH may be divided into 2 subsets: an early, indifferent stage of other histiocytic disorders and a specific condition without a subsequent disorder.1,9 GEH is generally not associated with malignancy and the characteristic regression has been postulated to be mediated by massive apoptotic cell death.15 As there are no clinical or histologic parameters that may predict a patient’s development of other, more severe forms of histiocytosis, close follow-up is essential.9 We noted the the symmetrical nature of the eruption both in the context of the papular component and erthrodermic element. In reviewing the literature, it would suggest that the appearance manifested by this case is typical for this disorder recognizing that typical is an oxymoron in the context of a condition that is so rare. Other forms of histiocytopathy do not have this distinctive pattern of papular erythroderma.
This article presents an exceptionally rare but classic presentation of GEH based on a careful integration of the clinical features, light microscopic findings and phenotypic profile.
Dr. Magro is the director of dermatopathology at Weill Cornell Medicine in New York, NY.
Dr. Kazi is a dermatology resident at Columbia Medical Center in New York, NY.
Dr. Bernert is a dermatopathologist at Arizona Dermatopathology (Aurora Diagnostics) in Scottsdale, AZ.
Dr. Moussa is a physician at LECOM/Alta Dermatology in Scottsdale, AZ.
Disclosure: The authors report no relevant financial relationships.
References
1. Cardoso F, Serafini NB, Reis BD, Nuñez MD, Nery JA, Lupi O. Generalized eruptive histiocytoma: a rare disease in an elderly patient. An Bras Dermatol. 2013;88(1):105-108.
2. Santegoets SJ, Gibbs S, Kroeze K, et al. Transcriptional profiling of human skin-resident Langerhans cells and CD1a+ dermal dendritic cells: differential states suggest distinct functions. J Leukoc Biol. 2008;84(1):143-151.
3. Verma SB. Generalized eruptive histiocytomas and juvenile eruptive xanthogranulomas in a 10-year-old boy: a potpourri of exotic terms indicating the need for unification. Int J Dermatol. 2012;51(4):445-447.
4. Purgina B, Jaffe R, Monaco SE, et al. Cytomorphology of Erdheim-Chester disease presenting as a retroperitoneal soft tissue lesion. Cyto J. 2011;8:22.
5. Perrin C, Michiels JF, Lacour JP, Chagnon A, Fuzibet JG. Sinus histiocytosis (Rosai-Dorfman disease) clinically limited to the skin: an immunohistochemical and ultrastructural study. J Cutan Pathol. 1993;20(4):368-374.
6. Singh NG, Mannan AA. Cutaneous Rosai-Dorfman disease: report of a case. Indian J Pathol Microbiol. 2013;56(1):60-61.
7. Sagransky M, Deng AC, Magro CM. Primary cutaneous Langerhans cell sarcoma: a report of four cases and review of the literature. Am J Dermatopathol. 2013;35(2):196-204.
8.Takahashi E, Nakamura S, Histiocytic sarcoma: an updated literature review based on the 2008 WHO classification. J Clin Exp Hematop. 2013;53(1):1-8.
9. Fernández-Jorge B, Goday-Buján J, Del Pozo Losada J, Alvarez-Rodriguez R, Fonseca E. A case of generalized eruptive histiocytosis. Acta Derm Venereol. 2007;87(6):533-536.
10. Wee SH, Kim HS, Chang SN, Kim DK, Park WH. Generalized eruptive histiocytoma: a pediatric case. Pediatr Dermatol. 2000;17(6):453-455.
11. Winkelmann RK, Muller SA. Generalized eruptive histiocytoma: a benign papular histiocytic reticulosis. Arch Dermatol. 1963;88:586-596.
12. Lan Ma H, Metze D, Luger TA, Steinhoff M. Successful treatment of generalized eruptive histiocytoma with PUVA. J Dtsch Dermatol Ges. 2007;5(2):131-134.
13. Klemke CD, Dippel E, Geilen CC, et al. Atypical generalized eruptive histiocytosis associated with acute monocytic leukemia. J Am Acad Dermatol. 2003;49(5 suppl):S233-S236.
14. Montero I, Gutiérrez-González R, Ginarte M, Toribio J. Generalized eruptive histiocytosis in a patient with chronic myelomonocytic leukemia. Actas Dermosifiliogr. 2012;103(7):643-644.
15. Tang X, Shen H, Xu A, et al. Spontaneous regression of generalized eruptive histiocytosis: possible involvement of apoptosis? Int J Dermatol. 2007;46(10):1073-1075.
A 23-year-old-man of Mexican descent presented in July of 2013 with an extensive papular eruption on his bilateral lower extremities. The papules ranged in size from 0.2 to 1.0 cm, both firm and soft, without scale or crust and were distributed symmetrically. The lesions were overlying a confluent, red-brown, smooth, erythematous skin with a serpiginous border extending from mid-calf up to his thighs, with trace pitting edema (Figures 1A-C).
Over the next several months, the papules spread from his posterior calvesup to his inguinal folds, increasing in size and number. He had no systemic signs or symptoms. The only medication that the patient took during this time was clonazepam, for a new diagnosis of anxiety. He did not try any topical or oral medications for the skin lesions. Besides anxiety, the patient also had a history of stress-induced urticaria. He had no family history of skin diseases. A limited battery of laboratory tests were performed in Mexico, revealing a complete blood count within normal limits, a metabolic panel showing hypoalbuminemia and a normal lipid profile. Viral serologies and an autoimmune workup were not performed. Imaging studies were within normal limits.
Biopsies of the patient’s lesions procured at different time points in the patient’s clinical course demonstrated an extensive dermal histiocytic infiltrate, accompanied by concomitant interstitial mucin deposition (Figures 2A-B). The histiocytoid cells ranged from being rounded and epithelioid to exhibiting a somewhat spindled appearance, especially at the base of the infiltrate. The cell nuclei were reniform and irregularly contoured in shape, with somewhat thickened nuclear membranes. There was a moderate degree of pleomorphism to the cell population, with some cells being quite large (50-100 µm), although the majority of the cells were monotypic, in the 12 to 15 µm size range (Figures 2C1-2). The cells had vesicular nuclei with multiple chromocenters and abundant eosinophilic to basophilic cytoplasm. The pleomorphism was less conspicuous at the base of the lesions. No significant mitotic activity was identified. Although the dominant histiocytic infiltrate was mononuclear, a few multinucleated cells were noted. There were many admixed neutrophils and plasma cells in the infiltrate, although without emperilopolesis by the larger histiocytic elements (Figure 3).
An extensive array of immunohistochemical stains were performed. The mucin deposition in the dermis was highlighted by an Alcian blue preparation. CD11c and CD14 stains highlighted the infiltrate (Figures 3 and 4). A CD1a preparation showed positivity amidst reactive Langerhans cells (LCs). There was extensive immunoreactivity of the histiocytes for CD43 and CD68 with a considerable degree of positivity amidst the deeper-seated, dendritic spindled elements. A myeloperoxidase preparation was positive amidst neutrophils, while the majority of the histiocytes were essentially negative. A CD79A highlighted reactive plasma cells. There was extensive staining throughout the infiltrate for factor XIIIa (Figure 5) and CD34. The staining intensity was quite varied ranging from being weakly to strongly positive. An S100 preparation showed positivity amidst a few of the larger elements noted superficially, while most of the infiltrate was negative. Significant immunoreactivity was not identified for CD30 or a pan-cytokeratin. Similarly, a Langerin stain was negative. There was also rather striking immunoreactivity of the infiltrate for CD34.
Discussion
The histiocytopathy syndromes are proliferative disorders of monocytes exhibiting varied terminal differentiation ranging from infiltrates of scavenger macrophage origin to a monocyte with dendritic cell (DC) properties. The macrophage has as its main function phagocytosis, while the DCs are further subcategorized according to their location in tissue and inherent antigen presenting properties.
DCs provide an essential link between innate and adaptive immunity by virtue of their antigen-presenting activity and cytokine production. The DCs can largely be divided into 3 subsets represented by the LCs, myeloid DCs (mDCs) and the plasmacytoid DCs (pDCs), respectively. The latter 2 DCs have also been designated DC1 and DC2, respectively. The mDCs exist in 3 main compartments: peripheral tissue DCs, secondary lymphoid organ resident DCs and circulating blood DCs. In the skin, the peripheral tissue DCs fall under the designation of dermal dendrocytes. Given a common CD34 positive stem cell origin for both LCs and mDCs, it is not surprising that the mDCs can differentiate into LCs.
The mDCs are characterized by the production of a large number of soluble factors including interleukin (IL)-6, IL-8, IL-10, IL-12, and the expression of toll-like receptors (TLR) 2, 4 and 7. A critical function of the mDCs is to prime T cells to help naïve B cells to produce large amounts of IgM and switch isotypes toward IgG and IgA. In contrast, LCs are not capable of regulating B cell differentiation; mDCs typically express a myeloid marker profile. In this regard, they are CD11c+ and lysozyme positive and show variable positivity for CD163 and CD68. They are typically myeloperoxidase negative.
In addition, more terminally differentiated myeloid markers such as CD14, CD83 and HLA-DR can be observed. The mDC is a somewhat malleable cell that can differentiate further to exhibit an overlapping phenotypic profile with the pDCs such as myxovirus resistance protein A (MxA), CD56 and CD123; as a result of this overlapping phenotypic profile these cells fall under the designation of an interferon dendritic cell (IF-DC). The resident dermal DCs is typically factor XIIIa positive and does not have any overlapping phenotypic features with a pDC and hence is not considered an IF-DC. The exact role of the peripheral blood mDCs is unclear; however, in human blood, the majority of the mDCs express BDCA-1 while a minor subset express BDCA-3. The third subset express neither BDCA-1 nor BDCA-3, although exhibit positivity for CD16.
In contrast, pDCs are characterized by their plasma cell-like morphology based primarily on the eccentric disposition of the nucleus, production of large amounts of type I interferons and expression of TLRs 7 and 9. They can express CD2 and CD7 along with MxA, an IF-alpha inducible protein and TCL1 oncogene; pDCs are characterized by their expression of CD123, although CD123 is not specific for pDCs. CD123, the IL-3 receptor, is found on various pluripotent hematopoietic precursor cells promoting specific lines of differentiation. One of the most specific antigens expressed by pDCs is CD303 (BDCDA2). Like the mDCs, they too may also express CD83, a cell surface molecule expressed by mature DCs. It should be noted that the exact lineage affiliation of pDCs remains undefined, although a lymphoid precursor seems likely. However, they are distinct from mDCs; they do not express myeloid specific markers such as lysozyme, myeloperoxidase and CD11c. They are BDCA-2 positive. Their main role is one related to enhancement of innate immunity through the elaboration of IF-alpha; pDCs are not involved in antigen processing.
Cutaneous clonal monocyte proliferations are derived from these aforesaid cell types and accordingly have been categorized into 3 classes based on the nature of the proliferating cell: Class I (LC histiocytosis), Class II (macrophage/dermal dendrocyte related histiocytoses) and Class III (malignant histiocytosis).1
In this case, histiocytes had a very distinctive phenotypic profile, whereby they were terminally differentiated CD14-positive monocytes that also showed immunoreactivity for CD68, CD11c and factor XIIIa, without positivity for CD83 and myeloperoxidase. A minor component of the histiocytic infiltrate, namely the somewhat pleomorphic multinucleated cell were S100 positive, although without any concomitant immunoreactivity of Langerin and CD1A. The CD34 preparation was difficult to interpret because of the extensive staining of the reticulin network and blood vessels. Overall, the phenotypic profile was compatible with a form of histiocytosis composed of resident dermal DC derivation.2
The factor XIIIa-positive, dermal dendritic histiocytopathies are defined by juvenile xanthogranuloma, xanthoma disseminatum, Rosai-Dorfman disease, generalized eruptive histiocytosis (GEH) and Erdheim-Chester disease. 3-5 The pleomorphism present amidst the histiocytes is quite characteristic for all factor XIIIa dermal dendritic histiocytopathies, and especially for juvenile xanthogranuloma and Rosai-Dorfman disease.3,5,6 In addition, the presence of other inflammatory cell elements, including plasma cells and neutrophils, is also an intrinsic feature of these diseases.3,5-7 There is considerable clinical and histopathologic overlap between these entities.
Another important differential diagnosis, which is not a Factor XIIIA-positive, dermal dendritic histiocytopathy, is histiocytic sarcoma. Histiocytic sarcoma is an extremely rare, malignant neoplasm exhibiting morphologic and immunophenotypic evidence of histiocytic differentiation. It is diagnosed on the basis of highly atypical morphology of tumor cells and expression of histiocyte-associated markers. Although the infiltrate in this case did have a moderately atypical morphology and did express histiocytic markers, the clinical presentation and regression of the lesions aid in the exclusion of the diagnosis of histiocytic sarcoma.8 All in all, the primarily monotypic histiocytic infiltrate, the immunohistochemical profile, the lack of staining for LC markers, the absence of xanthomatous cells and the clinical presentation including the regressive tendency of the lesions were most compatible with a diagnosis of GEH.7
GEH is a rare type of factor XIIIa-positive histiocytopathy, characterized by symmetric distribution of red-brown papules on the trunk, proximal extremities and face. The lesions tend to regress spontaneously, leaving behind hyperpigmented macules, a finding well exemplified by this case. It is primarily a disease of adults.9,10
GEH is an extremely rare, benign, non-LC histiocytosis, which was first described in 1963 by Wikelmann and Müller, amidst 3 adult patients.11 There have been a few cases described in children and overall, less than 50 cases have been reported worldwide. The onset of this disease in adults is typically in third to sixth decades of life; while in children, the commencement is before the age 4. GEH manifests in red to brown papules, typically less than 1.0 cm, distributed on the trunk, proximal extremities and occasionally, the face. The papules usually have a striking symmetrical disposition and rarely involve mucosal surfaces or viscera. Within several months, the lesions resolve, leaving behind hyperpigmented macules.1,11,12 The etiology of the condition is unknown but likely reflects a clonal disorder of myelomonocytic cells. It is unclear if GEH has the same association with underlying myeloproliferative disease as conditions such as histiocytosis X.7,13,14 Diagnosis is made based on histopathologic and immunohistochemical examination. We present a case of GEH in a 23-year-old man, with detailed focus on the clinical presentation and histopathology, in order to improve understanding of the diagnosis of this disease.
Recent medical literature has suggested that GEH may be divided into 2 subsets: an early, indifferent stage of other histiocytic disorders and a specific condition without a subsequent disorder.1,9 GEH is generally not associated with malignancy and the characteristic regression has been postulated to be mediated by massive apoptotic cell death.15 As there are no clinical or histologic parameters that may predict a patient’s development of other, more severe forms of histiocytosis, close follow-up is essential.9 We noted the the symmetrical nature of the eruption both in the context of the papular component and erthrodermic element. In reviewing the literature, it would suggest that the appearance manifested by this case is typical for this disorder recognizing that typical is an oxymoron in the context of a condition that is so rare. Other forms of histiocytopathy do not have this distinctive pattern of papular erythroderma.
This article presents an exceptionally rare but classic presentation of GEH based on a careful integration of the clinical features, light microscopic findings and phenotypic profile.
Dr. Magro is the director of dermatopathology at Weill Cornell Medicine in New York, NY.
Dr. Kazi is a dermatology resident at Columbia Medical Center in New York, NY.
Dr. Bernert is a dermatopathologist at Arizona Dermatopathology (Aurora Diagnostics) in Scottsdale, AZ.
Dr. Moussa is a physician at LECOM/Alta Dermatology in Scottsdale, AZ.
Disclosure: The authors report no relevant financial relationships.
References
1. Cardoso F, Serafini NB, Reis BD, Nuñez MD, Nery JA, Lupi O. Generalized eruptive histiocytoma: a rare disease in an elderly patient. An Bras Dermatol. 2013;88(1):105-108.
2. Santegoets SJ, Gibbs S, Kroeze K, et al. Transcriptional profiling of human skin-resident Langerhans cells and CD1a+ dermal dendritic cells: differential states suggest distinct functions. J Leukoc Biol. 2008;84(1):143-151.
3. Verma SB. Generalized eruptive histiocytomas and juvenile eruptive xanthogranulomas in a 10-year-old boy: a potpourri of exotic terms indicating the need for unification. Int J Dermatol. 2012;51(4):445-447.
4. Purgina B, Jaffe R, Monaco SE, et al. Cytomorphology of Erdheim-Chester disease presenting as a retroperitoneal soft tissue lesion. Cyto J. 2011;8:22.
5. Perrin C, Michiels JF, Lacour JP, Chagnon A, Fuzibet JG. Sinus histiocytosis (Rosai-Dorfman disease) clinically limited to the skin: an immunohistochemical and ultrastructural study. J Cutan Pathol. 1993;20(4):368-374.
6. Singh NG, Mannan AA. Cutaneous Rosai-Dorfman disease: report of a case. Indian J Pathol Microbiol. 2013;56(1):60-61.
7. Sagransky M, Deng AC, Magro CM. Primary cutaneous Langerhans cell sarcoma: a report of four cases and review of the literature. Am J Dermatopathol. 2013;35(2):196-204.
8.Takahashi E, Nakamura S, Histiocytic sarcoma: an updated literature review based on the 2008 WHO classification. J Clin Exp Hematop. 2013;53(1):1-8.
9. Fernández-Jorge B, Goday-Buján J, Del Pozo Losada J, Alvarez-Rodriguez R, Fonseca E. A case of generalized eruptive histiocytosis. Acta Derm Venereol. 2007;87(6):533-536.
10. Wee SH, Kim HS, Chang SN, Kim DK, Park WH. Generalized eruptive histiocytoma: a pediatric case. Pediatr Dermatol. 2000;17(6):453-455.
11. Winkelmann RK, Muller SA. Generalized eruptive histiocytoma: a benign papular histiocytic reticulosis. Arch Dermatol. 1963;88:586-596.
12. Lan Ma H, Metze D, Luger TA, Steinhoff M. Successful treatment of generalized eruptive histiocytoma with PUVA. J Dtsch Dermatol Ges. 2007;5(2):131-134.
13. Klemke CD, Dippel E, Geilen CC, et al. Atypical generalized eruptive histiocytosis associated with acute monocytic leukemia. J Am Acad Dermatol. 2003;49(5 suppl):S233-S236.
14. Montero I, Gutiérrez-González R, Ginarte M, Toribio J. Generalized eruptive histiocytosis in a patient with chronic myelomonocytic leukemia. Actas Dermosifiliogr. 2012;103(7):643-644.
15. Tang X, Shen H, Xu A, et al. Spontaneous regression of generalized eruptive histiocytosis: possible involvement of apoptosis? Int J Dermatol. 2007;46(10):1073-1075.
In this case, histiocytes had a very distinctive phenotypic profile, whereby they were terminally differentiated CD14-positive monocytes that also showed immunoreactivity for CD68, CD11c and factor XIIIa, without positivity for CD83 and myeloperoxidase. A minor component of the histiocytic infiltrate, namely the somewhat pleomorphic multinucleated cell were S100 positive, although without any concomitant immunoreactivity of Langerin and CD1A. The CD34 preparation was difficult to interpret because of the extensive staining of the reticulin network and blood vessels. Overall, the phenotypic profile was compatible with a form of histiocytosis composed of resident dermal DC derivation.2
The factor XIIIa-positive, dermal dendritic histiocytopathies are defined by juvenile xanthogranuloma, xanthoma disseminatum, Rosai-Dorfman disease, generalized eruptive histiocytosis (GEH) and Erdheim-Chester disease. 3-5 The pleomorphism present amidst the histiocytes is quite characteristic for all factor XIIIa dermal dendritic histiocytopathies, and especially for juvenile xanthogranuloma and Rosai-Dorfman disease.3,5,6 In addition, the presence of other inflammatory cell elements, including plasma cells and neutrophils, is also an intrinsic feature of these diseases.3,5-7 There is considerable clinical and histopathologic overlap between these entities.
Another important differential diagnosis, which is not a Factor XIIIA-positive, dermal dendritic histiocytopathy, is histiocytic sarcoma. Histiocytic sarcoma is an extremely rare, malignant neoplasm exhibiting morphologic and immunophenotypic evidence of histiocytic differentiation. It is diagnosed on the basis of highly atypical morphology of tumor cells and expression of histiocyte-associated markers. Although the infiltrate in this case did have a moderately atypical morphology and did express histiocytic markers, the clinical presentation and regression of the lesions aid in the exclusion of the diagnosis of histiocytic sarcoma.8 All in all, the primarily monotypic histiocytic infiltrate, the immunohistochemical profile, the lack of staining for LC markers, the absence of xanthomatous cells and the clinical presentation including the regressive tendency of the lesions were most compatible with a diagnosis of GEH.7
GEH is a rare type of factor XIIIa-positive histiocytopathy, characterized by symmetric distribution of red-brown papules on the trunk, proximal extremities and face. The lesions tend to regress spontaneously, leaving behind hyperpigmented macules, a finding well exemplified by this case. It is primarily a disease of adults.9,10
GEH is an extremely rare, benign, non-LC histiocytosis, which was first described in 1963 by Wikelmann and Müller, amidst 3 adult patients.11 There have been a few cases described in children and overall, less than 50 cases have been reported worldwide. The onset of this disease in adults is typically in third to sixth decades of life; while in children, the commencement is before the age 4. GEH manifests in red to brown papules, typically less than 1.0 cm, distributed on the trunk, proximal extremities and occasionally, the face. The papules usually have a striking symmetrical disposition and rarely involve mucosal surfaces or viscera. Within several months, the lesions resolve, leaving behind hyperpigmented macules.1,11,12 The etiology of the condition is unknown but likely reflects a clonal disorder of myelomonocytic cells. It is unclear if GEH has the same association with underlying myeloproliferative disease as conditions such as histiocytosis X.7,13,14 Diagnosis is made based on histopathologic and immunohistochemical examination. We present a case of GEH in a 23-year-old man, with detailed focus on the clinical presentation and histopathology, in order to improve understanding of the diagnosis of this disease.
Recent medical literature has suggested that GEH may be divided into 2 subsets: an early, indifferent stage of other histiocytic disorders and a specific condition without a subsequent disorder.1,9 GEH is generally not associated with malignancy and the characteristic regression has been postulated to be mediated by massive apoptotic cell death.15 As there are no clinical or histologic parameters that may predict a patient’s development of other, more severe forms of histiocytosis, close follow-up is essential.9 We noted the the symmetrical nature of the eruption both in the context of the papular component and erthrodermic element. In reviewing the literature, it would suggest that the appearance manifested by this case is typical for this disorder recognizing that typical is an oxymoron in the context of a condition that is so rare. Other forms of histiocytopathy do not have this distinctive pattern of papular erythroderma.
This article presents an exceptionally rare but classic presentation of GEH based on a careful integration of the clinical features, light microscopic findings and phenotypic profile.
Dr. Magro is the director of dermatopathology at Weill Cornell Medicine in New York, NY.
Dr. Kazi is a dermatology resident at Columbia Medical Center in New York, NY.
Dr. Bernert is a dermatopathologist at Arizona Dermatopathology (Aurora Diagnostics) in Scottsdale, AZ.
Dr. Moussa is a physician at LECOM/Alta Dermatology in Scottsdale, AZ.
Disclosure: The authors report no relevant financial relationships.
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15. Tang X, Shen H, Xu A, et al. Spontaneous regression of generalized eruptive histiocytosis: possible involvement of apoptosis? Int J Dermatol. 2007;46(10):1073-1075.
