Benjamin Kaffenberger, MD, Division of Dermatology; Kamruz Darabi, MD, Division of Dermatology, Division of Dermatopathology; Sara Peters, MD, Division of Dermatopathology; Jessica Kynyk, MD, Division of Pulmonary Medicine; Mark Bechtel, MD, Division of Pulmonary Medicine
All from Ohio State University College of Medicine, Columbus Ohio
Non-Langerhans cell histiocytoses were originally described as individual diagnoses. However, evidence has been mounting that these entities are manifestations on a spectrum of the same disease. The authors present a patient who initially presented with lymphadenopathy, pancytopenia, splenomegaly, and high-grade fevers. A bone marrow biopsy was performed and she was diagnosed with myelodysplastic syndrome with trisomy 8. Several months later, her persistent pulmonary lymphadenopathy was biopsied revealing Rosai-Dorfman disease. Two years after her initial hospitalization, the patient presented with lesions consistent with generalized eruptive histiocytomas. This case highlights the difficulty that clinicians encounter when trying to separate generalized eruptive histiocytomas, Rosai-Dorfman disease, and the other non-Langerhans cell histiocytoses. While further research needs to be performed in the field of histiocytoses, this case provides clinical support that these diseases are closely linked.
(J Clin Aesthet Dermatol. 2012;5(8):42–46.)
A 60-year-old Caucasian woman with a long history of unexplained lymphadenopathy was admitted to the hospital with worsening hilar lymphadenopathy, high-grade fevers, pancytopenia, and an absolute neutrophil count of 1500. Her erythrocyte sedimentation rate (ESR) was elevated at 76 and she had a notable ?-globulinopathy. A positron emission tomography/computed tomography (PET/CT) demonstrated increased metabolic activity in her bilateral femurs and tibias, widespread lymphadenopathy, and borderline hepatosplenomegaly. A bone marrow biopsy was performed and the patient was diagnosed with myelodysplastic syndrome (MDS), characterized as refractory cytopenia with multilineage dysplasia and ringed sideroblasts. Trisomy 8 was seen on chromosome analysis. An inguinal lymph node biopsy revealed sinus histiocytosis with positive S100 protein, and CD1a cell markers, the immunohistochemistry (IHC) of Langerhans cell histiocytosis (LCH). However, the sample lacked significant lymphocytic proliferation and eosinophils and these findings were felt to be secondary to the MDS. The patient defervesced without empiric antibiotics. Her cell counts recovered within the following week, except a persistent anemia. Her thrombocytopenia and leukopenia never recurred, and her anemia resolved after several months of darbepoetin treatment. She continued to follow with her pulmonologist for her abnormal chest CT, hilar lymphadenopathy, and patchy ground-glass opacities. Her disease progressed and due to clinical concern for sarcoidosis, connective tissue lung disease, or malignancy, she underwent mediastinoscopy. A lymph node resection of the right hilum showed sinus histiocytosis with positive S100 and CD68 expression and negative CD1a expression. Based on these findings, she was diagnosed with Rosai-Dorfman disease (RDD) six months after her hospitalization. A summary of the patient’s pathology reports are shown in Table 1. Two years after being diagnosed with MDS and 1.5 years after being diagnosed with RDD, the patient was seen in the university dermatology clinic for evaluation of scattered, noncoalescent flesh-colored and erythematous papules that had developed over the previous several months. The papules spread from her abdomen, superiorly to her thorax, neck, and across her upper extremity (Figure 1). The pathology under hematoxylin and eosin (H&E) staining and immunohistochemistry (IHC) is shown in Figure 2.
The patient in this case was diagnosed with RDD and, later, generalized eruptive histiocytomas (GEH), which are described as two separate non-Langerhans cell histiocytoses (nLCH) disorders. To the authors’ knowledge, this is the first time that multiple nLCH disorders have coexisted. The patient initially exhibited hilar lymphadenopathy, sinus histiocytosis, and IHC consistent with RDD. Her ?-globulinopathy and elevated ESR also may be seen in RDD. While RDD can be cutaneous, the lesions present were not consistent based on negative S100 protein staining (Table 2). GEH is a rare histiocytic process limited to the dermis; it was originally described in three adults in 1963. Table 2 contains six nLCH disorders that were considered in the differential diagnosis.
RDD and GEH are individually described entities within the histiocyte family. In these disorders, the underlying problem results from CD34+ myeloid progenitor cells and the numerous steps that are undertaken prior to presentation of disease in the skin, lymph nodes, or other internal organs.[2–3] An initial ordering system was suggested in 1987—class 1 includes LCH, class 2 includes nLCH, and class 3 includes malignant histiocytic disorders. However, several inconsistencies exist. Indeterminate cell histiocytosis (ICH) appears to bridge the gap between LCH and nLCH. ICH has identical IHC as LCH and can only be differentiated ultrastructurally.[5–6] In addition, RDD and LCH have presented concurrently in multiple cases adding to developing arguments for a spectrum of class 1 and 2 disease.7 Notably in this case, the patient’s initial lymph node biopsy was CD1a and S100 protein positive, which is consistent with LCH, not RDD. However, morphologically it did not appear to be typical LCH. This further supports the argument that the coexistence of possible class 1 and class 2 disease may be more common than previously thought. Within class 2 or the nLCH family, there are many classic and even more rare syndromes. Classic nLCH variants include generalized eruptive histiocytomas (GEH), sinus histiocytosis with massive lymphadenopathy or RDD, benign cephalic histiocytosis (BCH), xanthogranuloma (XG), papular xanthoma, xanthoma disseminatum (XD), and multicentric reticulohistiocytosis. While each entity was described separately, a consensus is developing that these nLCH disorders are a spectrum of one entity.[8–15] Members of the nLCH family can be difficult to distinguish due to the histopathological similarity of these entities. It is often impossible to render the histological diagnosis of multicentric reticulohistiocytosis, GEH, BCH, or XD without clinicopathological correlation.
Newer classification schemes attempt to prognosticate, stratifying based on maturity and thus the inverse correlation with the propensity to regress. Another scheme suggests that all dermal nLCH disorders are along the spectrum of XG because XG contains all five morphological appearances of histiocytes.[17–18] A review hypothesized that a XG and non-XG spectrum may adequately classify noncutaneous disease as well.19 Several case reports support this hypothesis after XG class disorders developed into another named disorder, including GEH developing into XD20 and BCH morphing into XG in two other patients.[21–22] Interestingly in this case, RDD would be classified in the non-XG class that Weitzman extrapolated from Zelger, whereas GEH is in the XG class.[17–19] It is unclear how much the initial MDS impacted the development of the nLCH disorders in this case.
Research recently has shown CD34+ cells with trisomy 8 from patients with MDS are resistant to apoptosis.23 These same CD34+ cells are accountable for histiocyte development. It is possible that the patient’s clone of CD34+ with trisomy 8 provided an overload of stem cells that developed into different histiocyte proliferations. It is also unclear when she first developed this abnormal clone of myeloid progenitors. Even though her cell counts had recovered and were stable when diagnosed with RDD and GEH, the nodal and skin proliferations likely resulted from a common precursor, secondary to her MDS. This case appears to suggest that individual members within the nLCH family are closely related and may indeed be a spectrum of diseases. However, further research is needed in the field of histiocytoses. It also provides further association of nLCH disorders with myeloid dysplasia.
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