The classification of the histiocytoses has evolved based on new understanding of the cell of origin as a bone marrow precursor. Although the pathologic features of the histiocytoses have not changed per se, molecular genetic information now needs to be integrated into the diagnosis. The basic lesions of the most common histiocytoses, their patterns in different sites, and ancillary diagnostics are now just one part of the classification. As more is understood about the cell of origin and molecular biology of the histiocytoses, future classifications will be refined.
Key points
- •
The histopathology and immunophenotype of the histiocytoses define the various families of lesions, LCH, JXG, ECD, and RDD.
- •
LCH is defined by histopathology and the immunophenotype CD1a/CD207 (Langerin)/S100 and the BRAF V600E mutation in more than half of cases.
- •
JXG is defined by histopathology and the immunophenotype CD14/CD68/CD163/Factor 13a/fascin but little S100 and no CD1a/CD207 or BRAF mutations.
- •
ECD is defined by clinical/radiographic features and JXG-type pathology with the BRAF V600E mutation in more than half of cases.
- •
RDD is defined by its histopathology with the RDD cell being selectively S100/fascin-positive.
- •
Understanding the cell of origin and integration of the molecular biology helps to further define these histiocytic lesions going forward, especially in cases where diagnostic LCH cells are not found.
Pathology of the histiocytoses
Current practice is to categorize the histiocytoses based on their histopathology into three basic families: (1) Langerhans cell histiocytosis (LCH), (2) juvenile xanthogranuloma family (JXG), and (3) Rosai-Dorfman disease (RDD). The histopathology superimposed with the clinical features and staging of the condition results in a final diagnosis, which accounts for most histiocytosis. There are instances of combined lesions either within the same site or at different sites in the same patient, which suggest that the histopathologic distinction does not strictly conform to the biology. This is best seen with LCH and Erdheim-Chester disease (ECD), which shares the histopathology of the JXG family; both conditions can occur in the same patient and both have a high incidence of BRAF mutations, even though these mutations are not a feature of the JXG family as a whole. Combined LCH and RDD or LCH and JXG in the same patient are increasingly recognized. Other more unusual histiocytic lesions include the LCH-like indeterminate cell histiocytosis, characterized by the presence of CD1a but a lack of CD207 or Birbeck granules. There are an insufficient number of cases to draw broad biologic conclusions that they differ markedly from LCH. A JXG-like systemic histiocytosis is the ALK-positive histiocytosis, most commonly in young females. It is defined by the presence of ALK mutations, including a rare example with a TPM3-ALK transcript. Again, there are too few cases for broad generalizations. For the purposes of this article, the pathology of the main histiocytoses families is contrasted, knowing that there is overlap.
Pathology of the histiocytoses
Current practice is to categorize the histiocytoses based on their histopathology into three basic families: (1) Langerhans cell histiocytosis (LCH), (2) juvenile xanthogranuloma family (JXG), and (3) Rosai-Dorfman disease (RDD). The histopathology superimposed with the clinical features and staging of the condition results in a final diagnosis, which accounts for most histiocytosis. There are instances of combined lesions either within the same site or at different sites in the same patient, which suggest that the histopathologic distinction does not strictly conform to the biology. This is best seen with LCH and Erdheim-Chester disease (ECD), which shares the histopathology of the JXG family; both conditions can occur in the same patient and both have a high incidence of BRAF mutations, even though these mutations are not a feature of the JXG family as a whole. Combined LCH and RDD or LCH and JXG in the same patient are increasingly recognized. Other more unusual histiocytic lesions include the LCH-like indeterminate cell histiocytosis, characterized by the presence of CD1a but a lack of CD207 or Birbeck granules. There are an insufficient number of cases to draw broad biologic conclusions that they differ markedly from LCH. A JXG-like systemic histiocytosis is the ALK-positive histiocytosis, most commonly in young females. It is defined by the presence of ALK mutations, including a rare example with a TPM3-ALK transcript. Again, there are too few cases for broad generalizations. For the purposes of this article, the pathology of the main histiocytoses families is contrasted, knowing that there is overlap.
General histopathology
Diagnosis of LCH requires a clonal neoplastic proliferation that expresses the immunohistochemical panel of CD1a, CD207 (Langerin), and S100 ( Fig. 1 ). About 60% of cases have a BRAF V600E mutation. The cells are generally large, 15 to 25 μm, round to oval in shape without the branching that characterizes inflammatory CD1a + dendritic cells. The nucleus has a complex contour with a “coffee-bean” nuclear groove (see Fig. 1 ). The CD207 immunostain has supplanted the need for electron microscopy ( Box 1 ). An inflammatory milieu of macrophages, eosinophils, and small lymphocytes is admixed with the LCH cells, but plasma cells are rare. Mitotic figures can at times be brisk but are not a cause for concern of Langerhans cell sarcoma unless there are atypical mitoses, marked pleomorphism, and frank cytologic atypia. LCH cells dual stained for Ki-67 and CD1a or CD207 have a proliferation rate of about 10% (Ronald Jaffe, MB,BCh, authors’ personal observation, 1985–2015). The appearance of LCH can vary by site and age of the lesion. Diagnostic challenge ensues when LCH cells are replaced by a fibroxanthomatous/inflammatory picture (false negative) and in chronic inflammatory processes in which the presence of CD1a + dendritic cells can confound (false positive) ( Box 1 ).
- •
Large (15–25 μm) oval, nondendritic cellular proliferation
- •
Complex, folded nuclear contour with “coffee-bean” groove
- •
Surface/paranuclear CD1a, granular cytoplasmic CD207 (Langerin), nuclear, and cytoplasmic S100.
JXG has an oval nucleus, inconspicuous nucleolus, and a variable amount of eosinophilic cytoplasm. The cells are variably spindled with the presence of multinucleated Touton giant cells typically present. The early JXG cell is more epithelioid and becomes progressively lipidized. The reticulohistiocytoma (oncocytic) variant is a large cell with abundant deeply eosinophilic cytoplasm. A lymphocytic interspersed component and occasionally, eosinophils, is typical. The result is that the JXG family of lesions can have a variety of appearances. The immunophenotype is fairly consistent but may vary with time: CD14/CD68/CD163/Factor 13a/fascin are all strongly expressed, except in purely xanthomatous cells that retain only CD68. CD1a and CD207 are absent, with light and variable staining for S100 in about 20% of cases. A panel is more convincing than any individual stain. The mitotic rate can vary, but is in the same range as LCH. A highly pleomorphic and cytologically atypical lesion with atypical mitoses but with the same immunophenotype is a histiocytic sarcoma with JXG phenotype.
RDD may be a phenotype that is common to several clinical conditions. Nodal sinus histiocytosis with massive lymphadenopathy is the prototype but extranodal disease is seen in greater than 40% of cases. Areas of RDD-type pathology have been seen in patients with autoimmune lymphoproliferative syndrome, Hodgkin lymphoma, HIV, and LCH. Plasma cells are usually abundant, and in about 20% of cases IgG4 predominance is found, with a possible association with IgG4-related disease in some cases. The histopathology of the autoinflammatory condition caused by mutation of the nucleoside transporter SLC29A3 is also that of RDD. The very large RDD cell has water-clear cytoplasm containing emperipolesis. Some RDD nuclei are very large, hypochromatic, and have a prominent nucleolus. The RDD cell selectively stains strongly for S100 and fascin in a cytoplasmic pattern that highlights the emperipolesis, with CD14/CD68 and variable CD163, whereas CD1a/CD207 are absent. Late RDD lesions are fibrosing and residual islands of RDD may be hard to find. Unlike LCH and JXG, there is no malignant counterpart.
Histopathology in specific organs
Bone
Osseous involvement is the quintessential LCH lesion presenting as a single lytic lesion or as a multiostotic, single system (SS) disease, but may also present as part of multisystem (MS) disease. Lytic skull lesions, especially of the calvaria and temporal bones, are a favored site and often involve the adjacent dura. Other osseous involvement includes vertebrae, jaws, ribs, pelvic bones, and proximal longs bones, but small bones of the hands and feet are spared. Involvement of central nervous system (CNS) “risk” bones (ie, temporal bones of the skull base, maxillofacial bones [sphenoid, ethmoid, and zygomatic], and orbital bones) are associated with higher risk of diabetes insipidus (DI), endocrinopathies, and/or CNS involvement, including late neurodegenerative sequelae. Chronic otitis or mastoiditis may herald involvement of the temporal bone and proptosis is present with orbital lesions. Bone pain is a common presentation. Neurologic defects may be present with vertebral collapse/vertebra plana when there is compression of the spinal cord. Loose teeth should raise the possibility of jaw involvement.
When undergoing biopsy procedures in the active phase, these lesions often show diffuse sheets of LCH cells and bone destruction ( Fig. 2 ). Immunostains confirm the diagnosis but rare cases may show only a minority of LCH cells displaying CD1a/CD207 ( Fig. 3 ). Later lesions may involute with fibrosis, xanthomatous histiocytes, scattered inflammatory cells, and retain only small pockets of LCH cells. At times extensive fibrosis in the absence of LCH cells precludes a definite diagnosis and chronic osteomyelitis, fibrohistiocytic lesions, or JXG may be considered. An inflammatory milieu is admixed with LCH cells, with macrophages, eosinophils, and lymphocytes. Multinucleated osteoclastic giant cells may also be present, which lack the grooved nuclei of the binucleated/multinucleated LCH cell (see Fig. 2 ). Plasma cells are rare in active LCH, but may be present after a pathologic fracture making distinction from chronic osteomyelitis or chronic recurrent multifocal osteomyelitis impossible in the absence of LCH cells. Histologically LCH can occasionally undergo aneurysmal bone cyst change.
RDD of the bone is usually diagnosed as an unexpected finding when LCH or osteomyelitis is suspected. It may cause initial confusion with LCH because of the S100 + cells but the large hypochromatic cells with emperipolesis should exclude LCH.
JXG can affect bones of any site and causes diagnostic confusion in the differential of a late sclerosing/involuting LCH lesion. It is usually part of a systemic JXG process and is rarely an isolated bone lesion. BRAF mutations are generally absent but the overlap with LCH is especially problematic in cases of JXG that develop after the treatment of LCH. Berres and colleagues showed two LCH cases in which subsequent pathology showed JXG pathology with a low level (0.03%–0.4%) of cells still showing a persistent BRAF V600E mutation. BRAF mutation status may provide better diagnostic clarity in the future for these challenging cases if the original LCH lesion was mutation positive.
ECD of bone is often suspected by virtue of the complicated clinical presentation with suggestive radiograph findings of bilateral long-bone osteosclerosis or retroperitoneal computed tomography/MRI findings. The histopathology of new lesions is that of a fibrosing lesion with the epithelioid JXG immunophenotype (CD14/CD68/CD163/F13a/fascin). CD1a and CD207 are absent, but S100 may be sparse and variable. Later lesions that are fibrotic and purely xanthomatous may have only CD68 expression. Like LCH, BRAF V600E mutation is seen in most cases.
Skin
Skin rash is a common presentation of LCH. In children it presents as a persistent seborrheic dermatitis or papulonodular eruption involving flexures (axilla, groin, and so forth) and the scalp. In neonatal LCH, nodular skin lesions and rash are the most common presentation. Although some neonatal skin disease may spontaneously regress (so-called Hashimoto-Pritzker disease or self-healing reticulohistiocytosis), careful staging is necessary to know which cases may actually have MS involvement because the histopathology is not predictive. Skin disease in adults is rare but presents as papulonodular eruptions or plaques over flexure sites and the scalp or as genital/perianal erosions. In children and adults, SS involvement of the skin may be the only presentation, but careful staging is needed to rule out MS involvement. In adults, skin LCH is also reported to have an increased risk of a subsequent hematologic malignancy.
Diffuse sheets of LCH cells often fill the papillary and/or deeper dermis. Immunostains highlight the lesional cells especially in cases with overlying ulceration ( Fig. 4 ). The differential diagnosis includes a chronic dermatitis with perivascular inflammation with a high content of CD1a + /CD207 − spindly dermal dendritic cells ( Fig. 5 ), a consequence of chronic scabies and postinfectious conditions. Immune defects, such as Omenn syndrome (OMIM #603554), may have S100 + dendritic cell hyperplasia. Nodular lesions should be distinguished from mastocytosis that expresses CD117 and tryptase. Immature myelomonocytic dermal infiltrates that express CD1a + are best diagnosed with a panel including CD14/lysozyme/MPO/CD68-KP1 (an early myeloid marker), and Ki-67, which is generally high.
JXG of the skin is more common than LCH, presenting as dermal and sometimes deep nodules. The diagnosis is confirmed by virtue of the histopathology and immunophenotype, CD14/CD68/CD163/F13a/fascin, without CD1a/CD207 and with low (variable to absent) S100. Dermal lesions tend to involute slowly over time. JXG lesions of the skin can follow treatment of LCH and rarely, combined elements of both are present. ECD can have a dermal component with xanthomatous papules or orbital xanthelasma, but the diagnosis should not be suggested unless there are other features. The presence of BRAF mutation, however, in a dermal JXG-type lesion in the correct context may raise concern for ECD.
RDD of the skin presents generally as a deep dermal mass lesion often with lymphoid follicles. The diagnosis is made by recognizing the characteristic RDD cells and confirming the immunophenotype with selective S100 and fascin immunostaining. Emperipolesis may be less prominent than in lymph nodes and late lesions are fibrosing, obscuring the residual islands of RDD. The differential diagnosis is from the reticulohistiocytoma JXG variant, which is superficial in the skin, lacking the strong S100 staining.
Lymph Nodes
LCH involvement in lymph nodes can be SS or part of MS disease. Patients present with asymptomatic localized lymphadenopathy. Histologic patterns vary but as a rule must contain a sinus element, highlighted with CD1a or CD207. In cases of paracortical infiltration by LCH, the cells are larger and have less expression of CD1a/CD207 compared with the sinus infiltrate. Atypical examples of nodal LCH include a high content of osteoclast-type giant cells, necrosis, and hemosiderin with less CD207 ( Fig. 6 ).
Late LCH of the lymph node may evolve to have no or very few CD1a + cells, replaced by a xanthomatous macrophage infiltrate, no longer diagnosable as LCH. Of note, JXG does not typically involve the lymph nodes. Rare examples of nodal “JXG” with cytologic atypia raise a suspicion for histiocytic sarcoma.
Needle biopsy may be informative if the sinus nature of the LCH infiltrate can be demonstrated. Caution with fine-needle aspiration requires the understanding that (1) not all nodal LCH cells express CD1a/CD207 with the same intensity, (2) endogenous medullary sinus cells can express CD207, and (3) dermatopathic lymphadenopathy with high CD1a/CD207 + population is excluded. Aspiration cytology may best be reserved for evaluating recurrence or disease extent rather than primary diagnosis.
There are no histologic features that predict systemic disease. Macrophage activation has been noted in nodes of multifocal and systemic disease, more commonly in young children with high-risk LCH and poor prognosis. There is no significant difference in the proliferation rate between SS and MS disease but there have been no well-designed studies investigating dual CD207/Ki-67 expression. Ki-67 proliferation index is quoted to be from 2.6% to 48%, although in our experience it is generally in the range of 10% or less in dual-stained cells.
An important differential diagnosis is with dermatopathic lymphadenopathy, which shows a nodular paracortical T-cell hyperplasia, expansion of S100 + /fascin + interdigitating dendritic cells, paracortical CD1a + /CD207 + Langerhans cells, along with macrophages containing melanin. The distinction from LCH includes the paracortical expansion, lack of sinus involvement, and high fascin positivity of the interdigitating dendritic cells ( Fig. 7 ). Also it is important to use both CD1a and CD207 in the lymph node because there are endogenous CD207 + /CD1a − cells in the medullary sinuses.
A differential diagnosis to consider especially in the adult is a primary Langerhans cell sarcoma. As a primary sarcoma, it is not preceded by LCH and has large, pleomorphic malignant cells with increased mitotic figures (more than 50 per 10 high power fields, Ki-67 >30%), many of which are atypical. The CD1a + /CD207 + /S100 + immunophenotype is preserved along with the sinus pattern. Expression of these markers can be variably lost with recurrences.
Other confounders in the lymph node are the histiocyte-rich variant of anaplastic large cell lymphoma, T-cell acute leukemia/lymphoma, granulomatous lymphadenitis, Churg-Strauss syndrome, and Kukuchi disease.
JXG and ECD rarely involve lymph nodes except by contiguous growth. RDD in the lymph node is the prototypical sinus histiocytosis with massive lymphadenopathy and relies on demonstrating the S100 + /fascin + RDD cells. There are examples of LCH and RDD in the same node or at different sites in the same patient ( Fig. 8 ).
High-Risk Organ Involvement
LCH involvement of the bone marrow, liver, and spleen are considered to be markers of higher risk of dying of disease (ie, risk organs). In multivariate analysis, pulmonary involvement was not an independent prognostic variable and is no longer included in the definition of risk organ involvement in MS-LCH.
Bone marrow
Although hematopoietic involvement in LCH is clinically defined by cytopenia of at least two cell lineages, it is exceptional to find marrow replacement by LCH. Rather when present, there are only a few small clusters of CD1a + /CD207 + cells (<10–20 CD1a + cells per slide) associated with more severe disease ( Fig. 9 ). Although the normal marrow biopsy should not have CD1a + /CD207 + cells, few CD1a + cells (<0.5%) may be detected by flow cytometry, but this does not indicate marrow LCH involvement. In aspirate cytology, distinguishing marrow involvement from lytic bone destruction should rest on finding accompanying hematopoietic elements in the former along with appropriate imaging ( Fig. 10 ). Staining with S100 should be avoided because stromal cells, lymphocytes, and dendritic cells can confound. Xanthomatous collections of CD163 + /CD68 + macrophages along with areas of stromal fibrosis may be seen, particularly in older lesions or after treatment, but aggregates of macrophages are also seen in active disease without CD1a + /CD207 + histiocytes ( Fig. 11 ). Conventionally, lack of CD1a + /CD207 + histiocytes is regarded as nondiagnostic for LCH. However, Berres and colleagues found the BRAF V600E mutation in CD34 + /CD207 − bone marrow progenitor cells in patients with systemic disease indicating that LCH progenitor cells are present. Evaluation of bone marrow involvement with sensitive polymerase chain reaction methods for the detection of BRAF V600E is needed to better define hemopoietic involvement in LCH patients because CD1a and CD207 are not reliable markers in the bone marrow. Lastly, the marrow may also be populated with activated CD163 + /CD68 + macrophages in cases of macrophage activation syndrome/hemophagocytic syndrome. The resultant cytokine storm is a possible underlying mechanism for cytopenias.
Related posts:
Dedication
Clinical Characteristics and Treatment of Langerhans Cell Histiocytosis
Strategies for the Prevention of Central Nervous System Complications in Patients with Langerhans Cell Histiocytosis
Congenital and Acquired Disorders of Macrophages and Histiocytes
Familial Hemophagocytic Lymphohistiocytosis
Pathogenesis of Hemophagocytic Lymphohistiocytosis
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
