Tables 1 and 2 list the clinical and pathologic features that help to describe and distinguish LCH from other, much rarer, histiocytic disorders. The CD1a+/CD207+ LC is the essential diagnostic feature in the histology of LCH. Mitoses are rare. Multinucleated giant cells may be present. Other inflammatory cells, such as granulocytes, eosinophils, macrophages, and lymphocytes, are also present in variable numbers. The diagnosis of LCH relies on the immunohistochemical identification of the presence of LC by characteristic appearance with reniform nuclei and CD1a+/CD207+ by immunohistochemistry (see Fig. 1A–E). Electron microscopy can identify Birbeck granules but is currently rarely used. Notably, CD207 expression levels may be variable within lesions and may be absent from liver, brain, or BM lesions. There are no predictive pathologic features that may define “favorable” or “unfavorable” histology. Immunohistochemistry, qualitative or quantitative PCR, and/or targeted sequencing may be used to identify BRAFV600E to support the diagnosis of LCH and also for risk-stratification. Additionally, high-sensitivity PCR of peripheral blood or BM mononuclear cells can identify BRAFV600E+ hematopoietic pre cursors, and the presence of which is associated with disseminated disease.
Table1. Clinical Features of the Non-Langerhans Cell Histiocytosis, Non-Hemophagocytic Lymphohistiocytoses
Table2. Histologic Features of Histiocytic Disorders
Fig1. HISTOLOGY OF LANGERHANS CELL HISTIOCYTOSIS (LCH), JUVENILE XANTHOGRANULOMA (JXG), HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS (HLH), ERDHEIM-CHESTER DISEASE (ECD), AND ROSAI-DORFMAN DISEASE (RDD). LCH: (A) Biopsy sample showing sheets of histiocytes with abundant pink cytoplasm and folded nuclei with prominent nuclear grooves. (B and C) Cells with a central longitudinal nuclear groove, giving the cell a coffee bean appearance. (D) Immunohistochemical stain for CD1A showing the histiocytic cells are positive. (E) Some cases of Langerhans histiocytosis are associated with prominent eosinophilia. JXG: Histologic features of juvenile xanthogranuloma vary. (F) In this case, low-power magnification shows a dome-shaped lesion with an attenuated epidermis. (G) At higher power, the bulk of the lesion is composed of a proliferation of histiocytes with abundant pink cytoplasm. Sometimes these histiocytes show more vacuolization or xanthomatization. (H) Scattered Touton-type giant cells are present. RDD: Low-power magnification of the biopsy sample (I) shows a mottled appearance of the lesion caused by dark areas containing small lymphocytes and lighter areas At higher magnification (J), the histiocytes have abundant pale cytoplasm with scattered cells within. This is emperipolesis, a process of cells traveling through the cytoplasm but not apparently becoming phagocytized or degraded. Note the plasma cells in the background. The emperipolesis can be better visualized with a CD68 stain for histiocytes (K). This process delineates the cell boundary and the cells within the histiocyte cytoplasm. The emperipolesis can also be seen on a Wright-stained touch preparation (L). HLH Illustrations from a 3-month-old girl who presented with diarrhea, pancytopenia, hepatomegaly, and liver failure. Bone marrow (M and N) showed left-shifted granulopoiesis and increased histiocytes, which at high power (O and P) were undergoing prominent phagocytosis of erythrocytes, platelets, and other cells. Liver biopsy sample (Q) showed a lymphohistiocytic infiltrate also associated with hemophagocytosis (R). The patient was shown to harbor a mutation of the perforin gene in exon 2. ECD: Lower magnification biopsy of skin from a patient involved by ECD characterize by dermal infiltrate (S) of bland appearing histiocytes characterized by abundant foamy (xanthomatous) cytoplasm with surrounding fibrosis. Note the multinucleated Touton giant cell in the inset. The cells are positive by histiocytic marker CD163 (T).
Patients who are suspected to have LCH or who have a new biopsy-proven diagnosis of LCH should have imaging to determine the extent of disease. Positron emission (PET) scanning is highly sensitive for LCH. Initial studies including a complete blood count, chemistries including liver function tests, coagulation workup, and urine osmolality are also warranted. Dental examination and radio graphs should also be considered depending on clinical history and exam. The occurrence of cytopenias, particularly thrombocytopenia, in the presence of liver or spleen involvement may suggest BM involvement. We typically perform BM studies for all patients under the age of two years old and patients with liver or spleen disease, regardless of complete blood count (CBC) results.
