Encyclopedia of Pathology

Living Edition
| Editors: J.H.J.M. van Krieken

Histiocytic Neoplasma

  • Stefano A. PileriEmail author
  • Valentina Tabanelli
  • Claudio Agostinelli
Living reference work entry
DOI: https://doi.org/10.1007/978-3-319-28845-1_3863-1

Introduction

In the fourth edition of the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues (Swerdlow et al. 2017), neoplasms derived from histiocytes and dendritic cells (HDCT) were gathered together based on the functional properties of their normal counterpart (i.e., phagocytosis, processing and presentation of antigens to lymphoid elements, etc.) more than histogenesis. In fact, although most of these elements derive from a common myeloid precursor, some recognize a mesenchymal origin (e.g., follicular dendritic cells). Importantly, HDCT tend to reproduce the morphologic, phenotypic, and ultrastructural characteristics of terminally differentiated elements, i.e., mature histiocytes and different categories of dendritic cells. In line with this, in the fourth edition of the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, blastic plasmacytoid dendritic cell tumor (Swerdlow et al. 2017; Marafioti et al. 2008) was excluded from the HDCT chapter and listed after acute myeloid leukemias and related precursor neoplasms, since it stems from a cell that acquires terminal differentiation and dendritic appearance following activation.

Intriguingly, during the last few years, several publications highlighted that – irrespective of their supposed normal counterpart (myeloid vs. mesenchymal) – some of these neoplasms are associated with or preceded by a malignant lymphoma (e.g., follicular lymphoma, chronic lymphocytic leukemia, B- or T-lymphoblastic lymphoma/leukemia, peripheral T-cell lymphoma) (Feldman et al. 2008; Chen et al. 2013; Shao et al. 2011; Ratei et al. 2010; Dalia et al. 2014a, b; Swerdlow et al. 2017). Under these circumstances, HDCT carry the same TR or IGH rearrangements and chromosomal aberrations as lymphoid neoplasms, this suggesting a process of transdifferentiation (Feldman et al. 2008; Chen et al. 2013; Shao et al. 2011; Ratei et al. 2010; Dalia et al. 2014a, b; Swerdlow et al. 2017; Facchetti et al. 2017). To date, neither comprehensive gene expression profiling nor next-generation sequencing studies have been carried out, except studies based on canine models (Boerkamp et al. 2014) and small series of follicular dendritic cell (FDC) sarcomas (Griffin et al. 2016; Hartmann et al. 2016; Laginestra et al. 2016; Facchetti et al. 2017). A next generation sequencing study of 13 FDC sarcomas revealed recurrent loss-of-function alterations in tumour suppressor genes involved in the negative regulation of NF-κB activation (38% of cases) and cell-cycle progression (31% of cases) (Griffin et al. 2016). The possible occurrence of BRAF V600E mutation has been reported in the setting of histiocytic sarcoma, Langerhans cell histiocytosis, FDC sarcoma, and disseminated juvenile xanthogranuloma (Go et al. 2014). In Erdheim–Chester disease, activating mutations in MAPK pathway genes, most notably BRAF V600E, as well as NRAS mutation, can be detected. Recurrent mutations in the PI3K pathway gene have also been described (Allen and Parson 2015).

Overall, HDCT are rare neoplasms corresponding to less than 1% of all tumors presenting in the lymph node and soft tissue. However, their exact prevalence is still unknown, since the term “histiocytic” was erroneously applied to malignant lymphomas for decades and some varieties of these tumors have only recently been identified (Dalia et al. 2014a, b; Falini et al. 1990; Pileri and Falini 1990). Their rarity is underlined by the fact that until now only a few large series have been reported in the literature (Dalia et al. 2014a; Pileri et al. 2002; Perkins and Shinohara 2013; Saygin et al. 2013; Facchetti et al. 2017). Importantly, HDCT should be differentiated from some regulatory disorders such as macrophage activation and hemophagocytic syndromes that contain a large amount of histiocytes but are not neoplastic (Falini et al. 1990; Pileri and Falini 1990).

In keeping with their rarity, the treatment of HDCT is extremely variable, no specific trials being available (Dalia et al. 2014a, b; Pileri et al. 2002; Donadieu et al. 2012; Facchetti et al. 2017; Swerdlow et al. 2017). In principles, excisional biopsies should be performed whenever possible, needle aspirates being indeed proscribed. Patients with one of these tumors have to be referred to a tertiary care center, where there is some experience on their management and therapy. An accurate staging is mandatory, since the distinction between localized and systemic forms impacts on therapeutic decisions. The former usually undergo surgical resection, the utility of radiotherapy and/or chemotherapy as adjuvant being debated (Dalia et al. 2014a, b; Pileri et al. 2002; Donadieu et al. 2012). The prognosis is quite favorable, also in case of relapses, recorded in at least one fourth of patients (Dalia et al. 2014a, b; Pileri et al. 2002; Donadieu et al. 2012). In contrast, widespread disease needs chemotherapy and has overall a poor prognosis. No unanimous view on the most effective schedule does exist (Dalia et al. 2014a, b; Pileri et al. 2002; Donadieu et al. 2012). Accordingly, CHOP, ICE, and ABVD have been used with variable results (Dalia et al. 2014a, b). More recently, the usage of BRAF and/or MAPK inhibitors has been proposed in tumours carrying gene mutations affecting this patway (Facchetti et al. 2017)

Histiocytic Sarcoma

Histiocytic sarcoma (HS) consists of elements provided with the morphologic and phenotypic characteristics of mature tissue histiocytes/macrophages (Swerdlow et al. 2017; Dalia et al. 2014a, b; Pileri et al. 2002; Takahashi and Nakamura 2013). The latter are derived from bone marrow (BM) and peripheral blood (PB) monocytes, and following migration/maturation in tissues participate in the innate response with pro- and anti-inflammatory cytokine effects as well as particulate removal by phagocytosis and tissue reconstitution (Swerdlow et al. 2017; Dalia et al. 2014a, b; Pileri et al. 2002; Takahashi and Nakamura 2013).

HS can affect patients at any age, although commoner in adults, with a slight male predominance (Swerdlow et al. 2017; Dalia et al. 2014a, b; Pileri et al. 2002; Takahashi and Nakamura 2013; Facchetti et al. 2017). It has been described to occur occasionally in association with mediastinal germ cell tumors, malignant lymphoma, myelodysplasia, and leukemia (Swerdlow et al. 2017; Dalia et al. 2014a, b; Pileri et al. 2002; Takahashi and Nakamura 2013; Facchetti et al. 2017). Notably, neoplastic proliferations associated with acute monoblastic leukemia are excluded from this setting (Swerdlow et al. 2017; Pileri et al. 2002).

The tumor more often develops at an extranodal site (e.g., intestine, skin, soft tissue, and bone) and rarely shows a systemic presentation (Swerdlow et al. 2017; Dalia et al. 2014a, b; Pileri et al. 2002; Takahashi and Nakamura 2013; Facchetti et al. 2017). In the latter case, the term malignant histiocytosis is sometimes applied (Swerdlow et al. 2017; Pileri et al. 2002). Fever and weight loss can occur (Swerdlow et al. 2017; Pileri et al. 2002).

Morphologically, HS consists of large elements that show a diffuse, non-cohesive growth pattern (Swerdlow et al. 2017; Dalia et al. 2014a, b; Pileri et al. 2002; Takahashi and Nakamura 2013; Facchetti et al. 2017). Intrasinusoidal diffusion is seen in the lymph node, liver, and spleen. The neoplastic elements are more often monomorphic with round-slightly indented, moderately atypical nuclei and a large rim of acidophilic cytoplasm (Fig. 1a). However, at times they are frankly malignant with spindle appearance (Fig. 1b). Giant cells are not infrequent. Mitotic figures are easily encountered. Phenomena of phagocytosis seldom occur. A variable number of reactive elements (i.e., small lymphocytes, neutrophils, eosinophils, and plasma cells) may be admixed.
Fig. 1

(a) Histiocytic sarcoma. Neoplastic cells display a centroblastic-like appearance. In contrast with true centroblasts, they have a larger rim of cytoplasm (hematoxylin and eosin, x200). (b) Histiocytic sarcoma. Another case provided with fusiform cells (hematoxylin and eosin, x200). (c) Histiocytic sarcoma. Neoplastic cells express CD68 (immunoalkaline phosphatase technique; Gill’s hematoxylin nuclear counterstain; PG-M1 monoclonal antibody; x200). (d) Histiocytic sarcoma. Neoplastic cells express CD163 (immunoperoxidase technique; Gill’s hematoxylin nuclear counterstain; x200). (e) Histiocytic sarcoma. Neoplastic cells express lysozyme (immunoalkaline phosphatase technique; Gill’s hematoxylin nuclear counterstain; x400). (f) Langerhans cell histiocytosis. Neoplastic cells show a bland morphology with infolded, coffee bean-shaped nuclei and a large rim of acidophilic cytoplasm (hematoxylin and eosin; x400). (g) Langerhans cell histiocytosis. Variable amounts of eosinophils, neutrophils, histiocytes, and small lymphocytes in the microenvironment (hematoxylin and eosin; x200). (h) Langerhans cell histiocytosis. Neoplastic cells are strongly S-100 positive (immunoalkaline phosphatase technique; Gill’s hematoxylin nuclear counterstain; x200). (i) Langerhans cell histiocytosis. Neoplastic cells express CD1a (immunoalkaline phosphatase technique; Gill’s hematoxylin nuclear counterstain; x200). (j) Langerhans cell histiocytosis. Langerin staining (immunoalkaline phosphatase technique; Gill’s hematoxylin nuclear counterstain; x200). (k) Langerhans cell sarcoma. Neoplastic cell shows overt cytological atypia and giant cells (hematoxylin and eosin; x200). (l) Interdigitating dendritic cell sarcoma. Neoplastic cells grow in bundles (hematoxylin and eosin, x200). Inset: positivity for protein S-100 (immunoalkaline phosphatase technique; Gill’s hematoxylin nuclear counterstain; x400)

Immunohistochemistry is of paramount diagnostic importance (Swerdlow et al. 2017; Dalia et al. 2014a, b; Pileri et al. 2002; Takahashi and Nakamura 2013; Facchetti et al. 2017). In particular, neoplastic cells strongly express lysozyme and CD68 (both in an intracytoplasmic granular fashion), as well as CD4, CD163, and in half cases protein S-100 (Fig. 1c–e). On the other hand, they lack B- and T-cell markers, CD30, EMA, CD21, CD23, CD35, CD1a, langerin, CD13, CD33, MPO, cytokeratins, and HMB45. At the ultrastructural level (Swerdlow et al. 2017; Pileri et al. 2002), they show numerous lysosomes, Birbeck granules, and junctions being absent. Clonal IGH or TR rearrangements have been recorded in a few cases that probably represent examples of transdifferentiation (Feldman et al. 2008). Some recent reports have pointed to the occurrence of BRAF (V600E) mutation in histiocytic sarcoma (Go et al. 2014; Idbaih et al. 2014; Facchetti et al. 2017), with dramatic response to vemurafenib in one instance (Idbaih et al. 2014). In one of these reports, the prevalence of the mutation in histiocytic sarcoma (62.5%) was even higher than that recorded in LCH (ranging from 25% to 60%, depending on the series), although it did not affect the clinical course of the disease (Go et al. 2014; Roden et al. 2014; Haroche et al. 2012; Sahm et al. 2012).

The clinical behavior of systemic forms is aggressive with a few patients alive at 5 years in spite of the chemotherapy (CHOP, ICE, or ABVD) used (Dalia et al. 2014a, b). Tumors presenting as localized masses seem to have a better outcome following resection associated or not with adjuvant radio- and/or chemotherapy (Swerdlow et al. 2017; Dalia et al. 2014a, b; Pileri et al. 2002). Because of limited experience, there is no treatment of choice (Dalia et al. 2014a, b; Pileri et al. 2002).

ALK-Positive Histiocytosis

In 2008, Chan et al. reported on a previously uncharacterized form of histiocytosis presenting in early infancy and showing ALK protein expression (Chan et al. 2008). The patients presented with pallor, massive hepatosplenomegaly, anemia, and thrombocytopenia. Liver biopsy revealed infiltration of the sinusoids by large histiocytes with markedly folded nuclei, fine chromatin, small nucleoli, and voluminous lightly eosinophilic cytoplasm that sometimes was vacuolated or contained phagocytized blood cells. One patient developed cutaneous infiltrates that morphologically resembled juvenile xanthogranuloma. The histiocytes stained for histiocytic markers (CD68, CD163, lysozyme), S100 protein, ALK (membranous and cytoplasmic pattern), and dendritic cell markers (fascin, factor XIIIa), but not CD1a and langerin. One case successfully analyzed by molecular techniques revealed TPM3-ALK fusion.

Tumors Derived from Langerhans Cells

Langerhans cells (LC) are BM-derived specialized dendritic cells located in mucosa sites/skin that upon activation become specialized for antigen presentation to T-lymphocytes and then migrate to the lymph node through lymphatics (Swerdlow et al. 2017; Dalia et al. 2014a, b; Badalian-Very et al. 2012; Kairouz et al. 2007).

Langerhans Cell Histiocytosis

Langerhans cell histiocytosis (LCH) is a clonal neoplastic proliferation of Langerhans-type cells (Swerdlow et al. 2017; Dalia et al. 2014a, b). It was variably termed in the past, this reflecting the histogenetic uncertainties that occurred for decades. It has an incidence of five new cases per 1,000,000 people per year and shows a strong predilection for male children (Swerdlow et al. 2017; Dalia et al. 2014a, b). The tumor can present in the form of a solitary lesion, of multiple lesions within the same anatomic system or as a multisystemic disease (Swerdlow et al. 2017; Dalia et al. 2014a, b; Pileri et al. 2002; Facchetti et al. 2017). A unifocal lesion more often affects older children or adults and does occur at the bone level by producing osteolysis or, less frequently, in the lymph node. Multifocal, unisystemic disease affects young children, the skull and mandibula being the commonest localizations. Cranial involvement can cause diabetes insipidus. Finally, multifocal, multisystemic LCH is observed in infants, showing an aggressive presentation (with fever, cytopenias, hepatosplenomegaly, skin and bone lesions) and poor prognosis. Pulmonary LCH is a polyclonal condition that is observed in heavy smokers and is felt to be reactive in nature (Beasley 2010; Juvet et al. 2010) as might be LCH foci at times found within the context of lymphomas and sarcomas (Benharroch et al. 2010). Such concept that is widely accepted in the literature has recently been challenged by the detection of homologous BRAF mutations in multiple foci of pulmonary LCH, a finding that instead suggests the clonal origin of the process at least in part of the cases (Roden et al. 2014; Yousem et al. 2013). Finally, LCH cases associated with lymphoblastic lymphoma/leukemia or peripheral B- or T-cell lymphoma and bearing the same IGH or TR rearrangement likely represent examples of transdifferentiation (Feldman et al. 2008; Dalia et al. 2014a, b).

Morphologically, neoplastic cells measure about 15 μm across and have an oval, grooved, folded, indented, or lobulated nucleus, fine chromatin, inconspicuous nucleoli, thin nuclear membrane, and a rather large rim of acidophilic cytoplasm, devoid of projections (Fig. 1f). Cytological atypia is usually minimal. Mitotic figures vary in number. Within this context, there are variable amounts of eosinophils, neutrophils, histiocytes, and small lymphocytes (Fig. 1g). Multinucleated giant cells can occur. Langerhans cells generally predominate with the exception of advanced stages of the disease that are characterized by prominent fibrosis. When lymph nodes and liver are involved, the process reveals a predominantly intrasinusoidal diffusion. In the spleen, it gives rise to nodular infiltrates.

Immunohistochemistry shows expression of CD1a, langerin, protein S-100, CD68, HLA-DR, and partly CD45 and lysozyme (Swerdlow et al. 2017; Dalia et al. 2014a, b; Pileri et al. 2002; Facchetti et al. 2017) (Fig. 1h–j). Electron microscopy reveals typical Birbeck granules. Clonality is demonstrated by the HUMARA test. During the last few years, several reports have highlighted the occurrence of the BRAF V600E or V600D mutation in a variable proportion of LCH cases (Go et al. 2014; Donadieu et al. 2012; Sahm et al. 2012; Juvet et al. 2010; Kansal et al. 2013) and subsequently in histiocytic and dendritic cell disorders other than LCH (Go et al. 2014). This finding can represent the rationale for the usage of vemurafenib in such setting (Donadieu et al. 2012).

The clinical outcome varies according to the stage (Swerdlow et al. 2017; Dalia et al. 2014a, b; Donadieu et al. 2012). Patients with unifocal disease have up to 99% survival, while those with multisystemic presentation more often die of LCH (Swerdlow et al. 2017; Dalia et al. 2014a, b; Donadieu et al. 2012). Therapy is limited to excision or radiation in patients with unifocal, unisystemic disease not affecting the CNS, liver, or spleen (Swerdlow et al. 2017; Dalia et al. 2014a, b; Donadieu et al. 2012). In cases with a single system involvement but multifocal lesions not affecting critical organs, corticosteroids are commonly used at least in the early phases of the disease (Dalia et al. 2014a, b; Donadieu et al. 2012). In subjects with LCH limited to the skin, topic nitrogen mustard, PUVA phototherapy, imiquimod, excimer laser, and radiotherapy represent further options (Dalia et al. 2014a, b). In all the remaining patients, systemic chemotherapy is applied according to the recommendations of the Histiocyte Society (Swerdlow et al. 2017; Donadieu et al. 2012).

Langerhans Cell Sarcoma

Langerhans cell sarcoma (LCS) is a rare high-grade tumor characterized by overt cytological malignancy and poor survival (Swerdlow et al. 2017; Dalia et al. 2014a, b; Pileri et al. 2002; Facchetti et al. 2017). It more often occurs in middle-aged women with multi-organ involvement (Swerdlow et al. 2017; Dalia et al. 2014a, b; Pileri et al. 2002). The skin, underlying soft tissue, and bone are the most commonly affected sites, followed by lymph nodes, liver, and spleen (Swerdlow et al. 2017; Dalia et al. 2014a, b; Pileri et al. 2002). While phenotype and ultrastructural features of LCS are the same as those of LCH, cell morphology is indeed different (Swerdlow et al. 2017; Dalia et al. 2014a, b; Pileri et al. 2002; Facchetti et al. 2017). In fact, the neoplastic population shows frank cytological atypia, prominent polymorphism, and abundant mitotic figures (Fig. 1k). Only a few elements reveal grooves. Multinucleated, giant cells are easily encountered. Eosinophils are scanty. Molecular biology studies are anecdotal. Chen et al. first reported on the occurrence of the BRAF E600V mutation in LCS as well as on the onset of the tumor in patients with a previous history of chronic lymphocytic leukemia, a finding suggesting transdifferentiation (Chen et al. 2013), an event that is also supported by other publications (Shao et al. 2011; Ratei et al. 2010). However, most information came from single case reports or very small series, thus hampering the knowledge of LCS both at the bio-pathological and clinical level. In general, the clinical behavior is aggressive with poor response to therapy and more than 50% mortality at 1 year. No established therapeutic schedule does exist, most cases being treated as aggressive lymphomas (Swerdlow et al. 2017; Dalia et al. 2014a, b; Pileri et al. 2002).

Interdigitating Dendritic Cell Sarcoma

The interdigitating cell (IDC) is derived from LC that travels to the lymph node where it acquires a paracortical/T-zone location (Swerdlow et al. 2017; Dalia et al. 2014a, b; Ohtake and Yamakawa 2013). It acts by presenting antigens to T-lymphocytes and regulating cellular immune response (Swerdlow et al. 2017; Dalia et al. 2014a, b; Ohtake and Yamakawa 2013).

Interdigitating dendritic cell sarcoma (IDCS) is a very rare condition that so far has been mainly the object of case reports (Swerdlow et al. 2017; Dalia et al. 2014a, b; Pileri et al. 2002; Ohtake and Yamakawa 2013; Facchetti et al. 2017). Two Surveillance, Epidemiology, and End Result studies identified about 120 cases in the literature (Perkins and Shinohara 2013; Saygin et al. 2013). It occurs more frequently in adults with a slight male predominance (Swerdlow et al. 2017; Dalia et al. 2014a, b; Takahashi and Nakamura 2013). Association with B- and T-cell lymphomas as well as with schizophrenia and tumors of the skin, liver, stomach, colon, breast, and brain has been recorded (Swerdlow et al. 2017; Dalia et al. 2014a, b; Pileri et al. 2002). Solitary lymph node involvement is most common, although extranodal localization in the skin and soft tissue has been reported (Swerdlow et al. 2017; Dalia et al. 2014a, b; Pileri et al. 2002). Patients more often present with a solitary asymptomatic mass but can at times reveal disseminated disease with systemic symptoms (Swerdlow et al. 2017; Dalia et al. 2014a, b; Pileri et al. 2002).

Morphologically (Swerdlow et al. 2017; Pileri et al. 2002; Ohtake and Yamakawa 2013; Facchetti et al. 2017) (Fig. 1l), IDCS usually forms fascicles with a storiform- or meningioma-like pattern that substitutes the paracortex, sparing normal follicles in the lymph node. Neoplastic cells may be either elongated or ovoid with dispersed chromatin and small-large distinct nucleoli. Cellular atypia is variable. The number of mitotic figures is moderate. Necrosis is usually absent. Numerous reactive lymphocytes can be admixed. The histological features may be indistinguishable from those of follicular dendritic cell sarcoma. Under these circumstances, the differential diagnosis is based on immunohistochemistry that displays positivities for protein S-100, vimentin, fascin, and variably CD68, CD45, CD4, and lysozyme. B- and T-cell markers as well as CD1a, langerin, CD21, CD23, CD35, CD30, EMA, CD34, MPO, and cytokeratins are negative (Swerdlow et al. 2017; Dalia et al. 2014a, b; Pileri et al. 2002; Facchetti et al. 2017) (Fig. 1l, inset). Electron microscopy reveals complex interdigitating processes in the absence of Birbeck granules and desmosomes (Swerdlow et al. 2017; Pileri et al. 2002). IGH or TR are in germ-line configuration with the exception of cases with a previous or concomitant B- or T-cell lymphoma, a finding strongly suggesting transdifferentiation (Chen et al. 2013; Shao et al. 2011; Dalia et al. 2014a, b; Ohtake and Yamakawa 2013). CGH studies have revealed some similarities with LCH (O’Malley et al. 2014). Weiss et al. carried a gene expression profiling analysis from a formalin-fixed, paraffin-embedded tissue sample and found overexpression of SPARC and HSP90 and the corresponding products that may represent the target for ad hoc therapies (Weiss et al. 2010).

The clinical course seems aggressive with about 50% of the patients dying of their disease (Swerdlow et al. 2017; Dalia et al. 2014a, b; Pileri et al. 2002). Only in cases with a solitary mass, surgery and/or radiotherapy can represent the first line of therapy (Swerdlow et al. 2017; Dalia et al. 2014a, b). In all patients with disseminated IDCS, chemotherapy is warranted. However, no consensus does exist as to the standard of care as well as to the role of autologous BM transplantation (Dalia et al. 2014a; Dalia et al. 2014b).

Follicular Dendritic Cell Sarcoma

Follicular dendritic cell sarcoma (FDCS) is a rare neoplasm consisting of elements with the morphologic and phenotypic characteristics of FDCs (Swerdlow et al. 2017; Feldman et al. 2008; Dalia et al. 2014a, b; Perkins and Shinohara 2013; Saygin et al. 2013; Ohtake and Yamakawa 2013; Facchetti et al. 2017). The latter are stromal-derived cells normally found in the germinal centers of lymph nodes as well as the extranodal ectopic lymphoid tissue (e.g., BM lymphoid nodules) (Swerdlow et al. 2017; Rezk et al. 2013). Via the formation of immune complexes, FDCs expose antigens to B cells playing a pivotal role for their proliferation and maturation, along with T-lymphocytes (Swerdlow et al. 2017; Rezk et al. 2013). Although FDCs are not derived from BM progenitors, being mesenchymal in nature, they express antigens related to BM stroma and can be clonally related to follicular lymphoma, possibly through a transdifferentiation process (Dalia et al. 2014a, b).

FDCS occurs at any age, although an adult predominance is observed (Swerdlow et al. 2017; Dalia et al. 2014a, b; Pileri et al. 2002). There is no sex predilection except for the inflammatory pseudotumor-like variant (Swerdlow et al. 2017). The latter most commonly affects females and is with a few exceptions associated with integration of EBV in a monoclonal episomal form, the virus entering via the expression of its receptor CD21 (Swerdlow et al. 2017; Dalia et al. 2014a, b; Facchetti et al. 2017). Occasionally, FDCS develops in the setting of Castleman disease (CD) or is associated with schizophrenia, paraneoplastic pemphigus, and myasthenia gravis (Swerdlow et al. 2017; Dalia et al. 2014a, b; Pileri et al. 2002; Facchetti et al. 2017). In case FDCS is associated with or preceded by CD, it arises in lymph nodes that usually harbor dysplastic FDC (Dalia et al. 2014a, b). In particular, FDCs of CD express epidermal growth factor receptor, which may promote FDC persistence and facilitate the onset of mutations that eventually result in FDCS (Dalia et al. 2014a, b).

In half to two third of patients, the tumor presents as isolated lymphadenopathy (Swerdlow et al. 2017; Dalia et al. 2014a, b; Pileri et al. 2002; Facchetti et al. 2017). Extranodal locations (in the tonsil, oral cavity, soft tissue, skin, liver, spleen, gastrointestinal tract, or mediastinum) can also occur (Swerdlow et al. 2017; Dalia et al. 2014a, b; Pileri et al. 2002; Facchetti et al. 2017). The mass tends to grow slowly and is painless unless it develops in the abdomen. Systemic symptoms are not observed with the exception of the inflammatory pseudotumor-like variant (Swerdlow et al. 2017).

At microscopic examination (Swerdlow et al. 2017; Dalia et al. 2014a, b; Pileri et al. 2002; Ohtake and Yamakawa 2013; Facchetti et al. 2017), FDCS consists of spindled to ovoid cells, forming fascicles, storiform arrays, whorls (at times reminiscent of the 360° pattern observed in meningioma), diffuse sheets, or vague nodules (Fig. 2a). The neoplastic cells generally reveal indistinct borders and a moderate amount of eosinophilic cytoplasm. The nuclei are oval or elongated, with finely dispersed chromatin, small but distinct nucleoli, and a delicate nuclear membrane. Nuclear pseudo-inclusions are common. Multinucleated giant tumor cells are frequently encountered. Significant cytological atypia is found in some cases, which display higher mitotic rates (>30 mitotic figures per 10 high-power fields vs. 0–10 in the ordinary cases), atypical mitoses, and coagulative necrosis (Fig. 2b). The tumor is typically slightly infiltrated by small lymphocytes (see below). Occasionally, neoplastic cells are scattered singly in a background of small lymphocytes, mimicking Hodgkin lymphoma. Rare cases may also show jigsaw puzzle-like lobulation and perivascular spaces, mimicking thymoma or carcinoma showing thymus-like element (CASTLE) (Swerdlow et al. 2017). Finally yet importantly, morphologic variants of FDCS have recently been reported: folliculotropic rich in B cells and angiomatoid, respectively (Lorenzi et al. 2012; Facchetti et al. 2017).
Fig. 2

(a) Follicular dendritic cell sarcoma. The growth pattern is reminiscent of the one observed in meningioma. Please, note the bland cytology (Giemsa staining; x200). (b) Follicular dendritic cell sarcoma. In an intra-abdominal mass measuring more than 6 cm across and characterized by multiple foci of necrosis, a frankly atypical population is seen (hematoxylin and eosin; x400). (c) Follicular dendritic cell sarcoma, inflammatory pseudotumor-like variant. Neoplastic cells are overwhelmed by inflammatory elements (hematoxylin and eosin; x400) and carry EBV infection (inset, EBER1/2 probes; in situ hybridization; x400). (d) Follicular dendritic cell sarcoma. Neoplastic cells express CD21 (immunoalkaline phosphatase technique; Gill’s hematoxylin nuclear counterstain; x400). (e) Follicular dendritic cell sarcoma. CD35 positivity (immunoalkaline phosphatase technique; Gill’s hematoxylin nuclear counterstain; x400). (f) Follicular dendritic cell sarcoma. CXCL13 staining (immunoperoxidase technique; Gill’s hematoxylin nuclear counterstain; x400). (g) Fibroblastic reticulum cell tumor. Neoplastic cells have a fusiform appearance (hematoxylin and eosin; x400). (h) Fibroblastic reticulum cell tumor. Neoplastic cells express smooth muscle actin (immunoalkaline phosphatase technique; Gill’s hematoxylin nuclear counterstain; x400). (i) Indeterminate dendritic cell tumor. The population has a Langerhans cell-like appearance (hematoxylin and eosin; x400). (j) Indeterminate dendritic cell tumor. S100 staining (immunoalkaline phosphatase technique; Gill’s hematoxylin nuclear counterstain; x400). (k) Disseminated juvenile xanthogranuloma. The growth consists of small cells, at times slightly spindled, with bland appearance (hematoxylin and eosin; x100). (l) Disseminated juvenile xanthogranuloma. CD68 expression (immunoalkaline phosphatase technique; Gill’s hematoxylin nuclear counterstain; PG-M1 monoclonal antibody; x400)

The inflammatory pseudotumor-like variant occurs exclusively as primary tumor in the liver or spleen (Swerdlow et al. 2017). The neoplastic spindled cells are dispersed within a prominent lymphoplasmacytic infiltrate (Fig. 2c).

Necrosis and hemorrhage are often present. The blood vessels frequently show fibrinoid deposits in the walls.

On immunophenotyping (Swerdlow et al. 2017; Dalia et al. 2014a, b; Pileri et al. 2002; Ohtake and Yamakawa 2013; Facchetti et al. 2017), neoplastic cells express CD21, CD23, CD35, CXCL13 (Vermi et al. 2008), clusterin, desmoplakin, vimentin, fascin, EGFR, HLA-DR, and the antigens detected by the monoclonal antibodies KIM4p and CNA.42 (Fig. 2d–f). Variably, they turn positive for EMA, protein S-100, and CD68 while exceptionally for CD20, CD45, CD30, and cytokeratins. CD1a, lysozyme, MPO, CD34, CD3, CD79a, and HMB45 are negative. The Ki-67 marking ranges from 1% to 75%. The admixed small lymphocytes show variable phenotype (B, T, or mixed).

Ultrastructurally, tumoral elements display long processes connected by scattered desmosomes. No Birbeck granules are seen. IGH or TR are in germ-line configuration unless the process is the result of transdifferentiation (Feldman et al. 2008; Shao et al. 2011; Dalia et al. 2014a, b). BRAF V600E mutation has at times been found (Go et al. 2014; Facchetti et al. 2017).

Recently, three reports have shed new light on the pathobiology of FDCS (Griffin et al. 2016; Hartmann et al. 2016; Laginestra et al. 2017). A targeted sequencing study revealed recurrent loss-of-function of tumor suppressor genes involved in the negative regulation of NF-κB (38%) and cell cycle (31%) (Griffin et al. 2016), including NFKBIA, CYLD, CDKN2A, and RB1. Focal copy number gain at 9p24 causing overexpression of CD274 (PD-L1) and PDCD1LG2 (PD-L2) was noted in three cases, which represents a well-known mechanism of immune evasion in cancer. Another study based on microRNA (miRNA) profiling of 31 FDCSs identified two subgroups with high and low miRNA expression levels, respectively (Hartmann et al. 2016). The former appeared closer to fibroblasts and myopericytomas, whereas the latter to FDCs from CD. High miRNA-expressing group presented a tendency to a shorter overall survival and more frequent podoplanin expression. Laginestra et al. (2016) analyzed the transcriptome of 29 FDCSs and compared it with that of other mesenchymal tumors (MTs), microdissected CD FDCs, and normal fibroblasts. The study demonstrated the transcriptional relationship of FDCSs with nonmalignant FDCs and their distinction from other MTs and fibroblasts. Furthermore, it provided evidence of a peculiar immunological microenvironment enriched in TFH and TREG populations, with special reference to the inhibitory immune receptor PD-1 and its ligands PD-L1 and PDL2.

The differential diagnosis of FDCS includes B- and T-cell lymphomas, myeloid sarcoma, melanoma, carcinomas, thymoma, blastic plasmacytoid dendritic cell neoplasm, and LCH/LCS. Rarely, peripheral nerve sheath tumors and malignant fibrous histiocytoma are mistaken for FDCS. Immunohistochemistry plays a basic role for the differentiation of FDCS from these entities (Dalia et al. 2014a, b).

The clinical behavior of FDCS is usually indolent. Most patients are treated by surgical excision followed or not by radiotherapy and/or chemotherapy (Swerdlow et al. 2017; Dalia et al. 2014a, b; Pileri et al. 2002; Facchetti et al. 2017). Local recurrences and metastases are recorded in 50% and 25% of patients, respectively (Swerdlow et al. 2017; Dalia et al. 2014a, b; Pileri et al. 2002). At least 10–20% of patients ultimately die of FDCS (Swerdlow et al. 2017; Dalia et al. 2014a, b; Pileri et al. 2002; Facchetti et al. 2017). Cases showing significant cytological atypia, extensive coagulative necrosis, high proliferation, size greater than 6 cm, and intra-abdominal location can run a rapidly fatal course (Swerdlow et al. 2017; Dalia et al. 2014a; Dalia et al. 2014b; Pileri et al. 2002; Facchetti et al. 2017). A lymphoma-like therapy is adopted in the latter cases, although no reference protocol does exist (Dalia et al. 2014a; b).

Other Rare Dendritic Cell Tumors

They may stem either from myeloid-derived dendritic cells (e.g., indeterminate dendritic cell tumor) or from stroma-derived dendritic cells (e.g., fibroblastic reticular cell tumor). Some dendritic cell neoplasms may remain unclassified even following extensive analysis or show hybrid features: these cases are tentatively termed “dendritic cell tumor, not otherwise specified” (Swerdlow et al. 2017).

Fibroblastic Reticulum Cell Tumor

This is an exceptional condition probably corresponding to what is reported as “cytokeratin-positive interstitial dendritic cell tumor” (Schuerfeld et al. 2003). Morphologically, fibroblastic reticulum cell tumor (FRCT) is undistinguishable from IDCS and FDCS (Swerdlow et al. 2017; Dalia et al. 2014a, b; Suárez-Vilela et al. 2012) (Fig. 2g). Immunohistochemistry, however, shows a distinctive profile with variable expression of smooth muscle actin, desmin, cytokeratin (in a dendritic pattern), factor XIIIa, and CD68. CD1a, protein S-100, CD21, CD23, CD35, desmoplakin, clusterin, and langerin are absent (Swerdlow et al. 2017; Dalia et al. 2014a, b; Suárez-Vilela et al. 2012) (Fig. 2h). Electron microscopy reveals delicate cytoplasmic extensions and features reminiscent of myofibroblasts (Swerdlow et al. 2017; Dalia et al. 2014a, b; Suárez-Vilela et al. 2012). Saygin et al. pooled 19 cases: their analysis showed that FRCT more often occurs in males aged 60 and presents in the lymph node, although extranodal locations can also be seen (Saygin et al. 2013). The outcome is variable: localized disease can be cured by surgery, while disseminated FRCT has a poor prognosis despite chemotherapy (Dalia et al. 2014a, b; Saygin et al. 2013).

Indeterminate Dendritic Cell Tumor

Indeterminate dendritic cell tumor (IDCT) is an extremely rare neoplasm. It stems from indeterminate cells, which are normally found in the dermis and might represent a form of mature LC (Dalia et al. 2014a, b). Actually, only case reports are available: thus, no conclusions can be drawn as to what the epidemiology of the tumor is concerned. Association with nodular scabies, pityriasis rosea, and indolent B-cell lymphomas has been observed (Dalia et al. 2014a, b). IDCT is characteristically located in the dermis by producing one or – more commonly – multiple generalized papules, nodules, or plaques. The tumor consists of spindled or ovoid elements with the same phenotypic profile as normal indeterminate dendritic cells. The morphology resembles the one of Langerhans cells (Swerdlow et al. 2017; Dalia et al. 2014a, b; Facchetti et al. 2017) (Fig. 2i). However, neoplastic elements lack Birbeck granules and langerin (Swerdlow et al. 2017; Dalia et al. 2014a, b; Facchetti et al. 2017). At times, they can acquire spindle appearance. The number of mitotic figures is variable. Multinucleated giant cells may be seen, while eosinophilic infiltrates are absent. Immunohistochemistry shows expression of CD1a and protein S-100 (Swerdlow et al. 2017; Dalia et al. 2014a, b; Facchetti et al. 2017) (Fig. 2j). The stains for B- and T-cell markers, CD21, CD23, CD35, CD30, and CD163 turn negative. CD45, CD68, lysozyme, and CD4 are variable as is the Ki-67 marking (Swerdlow et al. 2017; Dalia et al. 2014a, b; Facchetti et al. 2017). Electron microscopy display elongated processes in the absence of desmosomes (Swerdlow et al. 2017; Dalia et al. 2014a, b).

The behavior is variable: from spontaneous regression to rapid progression (Swerdlow et al. 2017; Dalia et al. 2014a, b). Association with indolent B-cell lymphoma and myeloid leukemia has anecdotally been reported, which might represent examples of transdifferentiation (Dalia et al. 2014a, b).

Disseminated Juvenile Xanthogranuloma

Disseminated juvenile xanthogranuloma (JXG) is a condition characterized by deep, visceral lesions similar to the one observed in dermal JXG (Swerdlow et al. 2017; Dalia et al. 2014a, b). It usually occurs in children (in 50% of cases during the first year of life) (Swerdlow et al. 2017; Dalia et al. 2014a, b).

Disseminated JXG may be associated with neurofibromatosis type 1 (NF1) (Swerdlow et al. 2017; Dalia et al. 2014a, b). Patients with both disseminated JXG and NF1 have a slightly increased risk to develop juvenile myelomonocytic leukemia (Swerdlow et al. 2017).

The most commonly affected sites are the skin and soft tissues, followed by mucosal surfaces, especially of the upper aerodigestive tract (Swerdlow et al. 2017; Dalia et al. 2014a, b). The central nervous system, dura, pituitary stalk, and brain can be interested as well as the eye, liver, lung, lymph node, and bone marrow (Swerdlow et al. 2017; Dalia et al. 2014a, b).

Morphologically (Swerdlow et al. 2017; Dalia et al. 2014a, b), JXG cells are small and oval, sometimes slightly spindled with a bland round-oval nucleus without grooves and pink cytoplasm (Fig. 2k). Giant Touton cells are less common at non-dermal sites. The cells become progressively lipidized (xanthomatous). A mixed inflammatory component is always detected.

Although JXG elements express a histiocytic phenotype with positivities for CD14, CD68, CD163, and Stabilin-1 (MS-1 antigen) (Fig. 2l), the histogenesis of the disease is still a matter of debate (Swerdlow et al. 2017; Dalia et al. 2014a, b). Factor XIIIa staining is common but not universal, fascin stains the cell cytoplasm, and S100 is variably positive in less than 20%. CD1a and langerin are negative (Swerdlow et al. 2017; Dalia et al. 2014a,b). IGH or TR are in germ-line configuration. Evidence for clonality has been detected in some instances (Swerdlow et al. 2017).

All clinical forms are benign, though multiple lesions in brain, dura, or pituitary can cause local consequences and even death (Swerdlow et al. 2017; Dalia et al. 2014a,b). Systemic forms that involve liver and BM have been treated with LCH-type therapy (Swerdlow et al. 2017; Dalia et al. 2014a, b).

Erdheim-Chester Disease

Erdheim–Chester disease (ECD) is a clonal systemic proliferation of histiocytes, commonly having a foamy (xanthomatous) component, and containing Touton giant cells (considered to be a non–Langerhans cell histiocytosis). However, as many as 20% of patients with ECD also have Langerhans cell histiocytosis lesions, and infiltration by ECD and Langerhans cell histiocytosis may be present within the same biopsies (Swerdlow et al. 2017; Wilejto and Abla 2012).

ECD is a rare condition. To date, < 1000 cases have been reported. The mean patient age at diagnosis is 55–60 years, but rare pediatric cases have also been reported. The male-to-female ratio is 3:1.

Virtually any organ or tissue can be infiltrated by ECD. Skeletal involvement occurs in most if not all cases. Cardiovascular involvement probably occurs in about 50% of patients but is likely underdiagnosed. One third of patients have retroperitoneal involvement. CNS involvement, diabetes insipidus, and/or exophthalmos occur in 20–30% of patients. CNS involvement may occur due to tissue infiltration by histiocytes or degenerative alterations typically affecting the cerebellum, with involvement due to degenerative alterations being much more difficult to treat. Xanthelasma, generally involving the eyelids or periorbital spaces, is the most common cutaneous manifestation.

The clinical course of ECD depends on the extent and distribution of the disease. Some cases, with lesions limited to the bone, are asymptomatic; others, with multisystemic disease, may follow an aggressive, rapid clinical course.

Morphologically and phenotypically, ECD is indeed similar to JDX. However, fibrosis is present in most cases and is sometimes abundant.

In several cases, clonality has been identified by classic cytogenetics and other techniques. Activating mutations in MAPK pathway genes, most notably BRAF V600E (reported in > 50% of cases), as well as NRAS mutation (recorded in ∼4% of cases), can be detected in ECD (Allen and Parsons 2015; Haroche et al. 2012). Recurrent mutations in the PI3KCA pathway gene have also been described (in ∼11% of cases) (Allen and Parsons 2015).

ECD is a chronic disease. The disease outcome correlates with sites of involvement; patients with CNS disease or multisystemic disease have a worse outcome (Swerdlow et al. 2017). Disease activity is assessed by clinical examination, imaging, and C reactive protein values, but no disease activity score has been established. Vemurafenib, an inhibitor of BRAF that is approved for treating patients with metastatic melanoma and BRAF V600 mutations, has recently been used, with promising results (Cohen-Aubart et al. 2014; Campochiaro et al. 2015).

References and Further Reading

  1. Allen, C.E, & Parsons, D.W. (2015). Biological and clinical significance of somatic mutations in Langerhans cell histiocytosis and related histiocytic neoplastic disorders. Hematology, American Society of Hematology Educational Programme, 2015, 559–64.Google Scholar
  2. Badalian-Very, G., Vergilio, J. A., Degar, B. A., Rodriguez-Galindo, C., & Rollins, B. J. (2012). Recent advances in the understanding of Langerhans cell histiocytosis. British Journal of Haematology, 156, 163–172.CrossRefGoogle Scholar
  3. Beasley, M. B. (2010). Smoking-related small airway disease – a review and update. Advances in Anatomic Pathology, 17, 270–276.CrossRefGoogle Scholar
  4. Benharroch, D., Guterman, G., Levy, I., & Shaco-Levy, R. (2010). High content of Langerhans cells in malignant lymphoma – incidence and significance. Virchows Archives, 457, 63–67.CrossRefGoogle Scholar
  5. Boerkamp, K. M., van der Kooij, M., van Steenbeek, F. G., et al. (2013). Gene expression profiling of histiocytic sarcomas in a canine model: The predisposed flatcoated retriever dog. PLoS One, 8, e71094.CrossRefGoogle Scholar
  6. Campochiaro C, Tomelleri A, Cavalli G, et al. (2015). Erdheim-Chester disease. European Journal of Internal Medicine, 26, 223–229.Google Scholar
  7. Chan, J. K., Lamant, L., Algar, E., et al. (2008). ALK+ histiocytosis: A novel type of systemic histiocytic proliferative disorder of early infancy. Blood, 112, 2965–2968.CrossRefGoogle Scholar
  8. Chen, W., Jaffe, R., Zhang, L., et al. (2013). Langerhans cell sarcoma arising from chronic lymphocytic lymphoma/small lymphocytic leukemia: Lineage analysis and BRAF V600E mutation study. North American Journal of Medical Sciences, 5, 386–391.CrossRefGoogle Scholar
  9. Cohen-Aubart, F., Emile, J. F., Maksud, P., et al. (2014). Marked efficacy of vemurafenib in suprasellar Erdheim-Chester disease. Neurology, 83, 1294–1296.CrossRefGoogle Scholar
  10. Dalia, S., Jaglal, M., Chervenick, P., Cualing, H., & Sokol, L. (2014a). Clinicopathologic characteristics and outcomes of histiocytic and dendritic cell neoplasms: The Moffitt cancer center experience over the last twenty-five years. Cancers, 6, 2275–2295.CrossRefGoogle Scholar
  11. Dalia, S., Shao, H., Sagatys, E., Cualing, H., & Sokol, L. (2014b). Dendritic cell and histiocytic neoplasms: Biology, diagnosis, and treatment. Cancer Control, 21, 290–300.CrossRefGoogle Scholar
  12. Donadieu, J., Chalard, F., & Jeziorski, E. (2012). Medical management of langerhans cell histiocytosis from diagnosis to treatment. Expert Opinion on Pharmacotherapy, 13, 1309–1322.CrossRefGoogle Scholar
  13. Falini, B., Pileri, S., De Solas, I., et al. (1990). Peripheral T-cell lymphoma associated with hemophagocytic syndrome. Blood, 75, 434–444.PubMedGoogle Scholar
  14. Facchetti, F., Pileri, S.A., Lorenzi, L., et al. (2017). Histiocytic and dendritic cell neoplasms: what have we learnt by studying 67 cases. Virchows Archives, 371, 467–489Google Scholar
  15. Feldman, A. L., Arber, D. A., Pittaluga, S., et al. (2008). Clonally related follicular lymphomas and histiocytic/dendritic cell sarcomas: Evidence for trans-differentiation of the follicular lymphoma clone. Blood, 111, 5433–5439.CrossRefGoogle Scholar
  16. Go, H., Jeon, Y. K., Huh, J., Choi, S. J., Choi, Y. D., Cha, H. J., Kim, H. J., Park, G., Min, S., & Kim, J. E. (2014). Frequent detection of BRAF(V600E) mutations in histiocytic and dendritic cell neoplasms. Histopathology, 65, 261–272.CrossRefGoogle Scholar
  17. Griffin, G.K., Sholl, L.M., Lindeman, N.I., et al. (2016). Targeted genomic sequencing of follicular dendritic cell sarcoma reveals recurrent alterations in NF-κB regulatory genes. Modern Pathology, 29, 67–74.Google Scholar
  18. Haroche, J., Charlotte, F., Arnaud, L., et al. (2012). High prevalence of BRAF V600E mutations in Erdheim-Chester disease but not in other non-Langerhans cell histiocytoses. Blood, 120, 2700–2703.CrossRefGoogle Scholar
  19. Hartmann, S., Döring, C., Agostinelli, C., et al. (2016). miRNA expression profiling divides follicular dendritic cell sarcomas into two groups, related to fibroblasts and myopericytomas or Castleman’s disease. European Journal of Cancer, 64, 159–66.Google Scholar
  20. Idbaih, A., Mokhtari, K., Emile, J. F., et al. (2014). Dramatic response of a BRAF V600E-mutated primary CNS histiocytic sarcoma to vemurafenib. Neurology, 83, 1478–1480.CrossRefGoogle Scholar
  21. Juvet, S. C., Hwang, D., & Downey, G. P. (2010). Rare lung diseases III: Pulmonary Langerhans’ cell histiocytosis. Canadian Respiratory Journal, 17, e55–e62.CrossRefGoogle Scholar
  22. Kairouz, S., Hashash, J., Kabbara, W., McHayleh, W., & Tabbara, I. A. (2007). Dendritic cell neoplasms: An overview. American Journal of Hematology, 82, 924–928.CrossRefGoogle Scholar
  23. Kansal, R., Quintanilla-Martinez, L., Datta, V., Lopategui, J., Garshfield, G., & Nathwani, B. N. (2013). Identification of the V600D mutation in exon 15 of the BRAF oncogene in congenital, benign Langerhans cell histiocytosis. Genes, Chromosomes and Cancer, 52, 99–106.CrossRefGoogle Scholar
  24. Laginestra, M.A., Tripodo, C., Agostinelli, C., et al. (2017). Distinctive histogenesis and immunological microenvironment based on transcriptional profiles of follicular dendritic cell sarcomas. Molecular Cancer Research, 5, 541–52.Google Scholar
  25. Lorenzi, L., Lonardi, S., Petrilli, G., et al. (2012). Folliculocentric B-cell-rich follicular dendritic cells sarcoma: A hitherto unreported morphological variant mimicking lymphoproliferative disorders. Human Pathology, 43, 209–215.CrossRefGoogle Scholar
  26. Marafioti, T., Paterson, J. C., Ballabio, E., et al. (2008). Novel markers of normal and neoplastic human plasmacytoid dendritic cells. Blood, 111, 3778–3792.CrossRefGoogle Scholar
  27. Méhes, G., Irsai, G., Bedekovics, J., et al. (2014). Activating BRAF V600E mutation in aggressive pediatric Langerhans cell histiocytosis: Demonstration by allele-specific PCR/direct sequencing and immunohistochemistry. American Journal of Surgical Pathology, 38, 1644–1648.CrossRefGoogle Scholar
  28. O’Malley, D. P., Zuckerberg, L., Smith, L. B., et al. (2014). The genetics of interdigitating dendritic cell sarcoma share some changes with Langerhans cell histiocytosis in select cases. Annals of Diagnostic Pathology, 18, 18–20.CrossRefGoogle Scholar
  29. Ohtake, H., & Yamakawa, M. (2013). Interdigitating dendritic cell sarcoma and follicular dendritic cell sarcoma: Histopathological findings for differential diagnosis. Journal of Clinical and Experimental Hematopathology, 53, 179–184.CrossRefGoogle Scholar
  30. Perkins, S. M., & Shinohara, E. T. (2013). Interdigitating and follicular dendritic cell sarcomas: A SEER analysis. American Journal of Clinical Oncology, 36, 395–398.CrossRefGoogle Scholar
  31. Pileri, S., & Falini, B. (1990). Peripheral T-cell lymphoma associated with hemophagocytic syndrome and hemophagocytic lymphohistiocytosis of children: Do they share something? Blood, 76, 2163–2164.Google Scholar
  32. Pileri, S. A., Grogan, T. M., Harris, N. L., et al. (2002). Tumours of histiocytes and accessory dendritic cells: An immunohistochemical approach to classification from the International Lymphoma Study Group based on 61 cases. Histopathology, 41, 1–29.CrossRefGoogle Scholar
  33. Ratei, R., Hummel, M., Anagnostopoulos, I., et al. (2010). Common clonal origin of an acute B-lymphoblastic leukemia and a Langerhans’ cell sarcoma: Evidence for hematopoietic plasticity. Haematologica, 95, 1461–1466.CrossRefGoogle Scholar
  34. Rezk, S. A., Nathwani, B. N., Zhao, X., & Weiss, L. M. (2013). Follicular dendritic cells: Origin, function, and different disease-associated patterns. Human Pathology, 44, 937–950.CrossRefGoogle Scholar
  35. Roden, A. C., Hu, X., Kip, S., et al. (2014). BRAF V600E expression in Langerhans cell histiocytosis: Clinical and immunohistochemical study on 25 pulmonary and 54 extrapulmonary cases. American Journal of Surgical Pathology, 38, 548–551.CrossRefGoogle Scholar
  36. Sahm, F., Capper, D., Preusser, M., et al. (2012). BRAFV600E mutant protein is expressed in cells of variable maturation in Langerhans cell histiocytosis. Blood, 120, e28–e34.CrossRefGoogle Scholar
  37. Saygin, C., Uzunaslan, D., Ozguroglu, M., Senocak, M., & Tuzuner, N. (2013). Dendritic cell sarcoma: A pooled analysis including 462 cases with presentation of our case series. Critical Reviews in Oncology/Hematology, 88, 253–271.CrossRefGoogle Scholar
  38. Schuerfeld, K., Lazzi, S., de Santi, M. M., Gozzetti, A., Leoncini, L., & Pileri, S. A. (2003). Cytokeratin-positive interstitial cell neoplasm: A case report and classification issues. Histopathology, 43, 491–494.CrossRefGoogle Scholar
  39. Shao, H., Xi, L., Raffeld, M., Feldman, A. L., et al. (2011). Clonally related histiocytic/dendritic cell sarcoma and chronic lymphocytic leukemia/small lymphocytic lymphoma: A study of seven cases. Modern Pathology, 24, 1421–1432.CrossRefGoogle Scholar
  40. Suárez-Vilela, D., Izquierdo, F. M., Méndez-Alvarez, J. R., & Escobar-Stein, J. (2012). Neoplasms of dendritic cells: Related cell origins and diagnostic markers. Fibroblastic reticulum cells and fibroblastic reticulum cell tumors show several immunophenotypic profiles. Human Pathology, 43, 1530–1531.CrossRefGoogle Scholar
  41. Swerdlow, S. H., Campo, E., Harris, N. L., Jaffe, E. S., Pileri, S. A., Stein, H., & Thiele, J. (Eds.). (2017). WHO classification of tumours of haematopoietic and lymphoid tissue. Revised 4th edition. Lyon: IARC Press. Chapter 17.Google Scholar
  42. Takahashi, E., & Nakamura, S. (2013). Histiocytic sarcoma: An updated literature review based on the 2008 WHO classification. Journal of Clinical and Experimental Hematopathology, 53, 1–8.CrossRefGoogle Scholar
  43. Vermi, W., Lonardi, S., Bosisio, D., et al. (2008). Identification of CXCL13 as a new marker for follicular dendritic cell sarcoma. Journal of Pathology, 216, 356–364.CrossRefGoogle Scholar
  44. Weiss, G. J., Alarcon, A., Halepota, M., Penny, R. J., & Von Hoff, D. D. (2010). Molecular characterization of interdigitating dendritic cell sarcoma. Rare Tumors, 2, e50.CrossRefGoogle Scholar
  45. Wilejto, M., & Abla, O. (2012). Langerhans cell histiocytosis and Erdheim-Chester disease. Current Opinion in Rheumatology, 24, 90–96.CrossRefGoogle Scholar
  46. Yousem, S. A., Dacic, S., Nikiforov, Y. E., & Nikiforova, M. (2013). Pulmonary Langerhans cell histiocytosis: Profiling of multifocal tumors using next-generation sequencing identifies concordant occurrence of BRAF V600E mutations. Chest, 143, 1679–1684.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Stefano A. Pileri
    • 1
    • 2
    Email author
  • Valentina Tabanelli
    • 2
  • Claudio Agostinelli
    • 3
  1. 1.Bologna UniversityBolognaItaly
  2. 2.European Institute of OncologyMilanItaly
  3. 3.Department of Experimental, Diagnostic and Specialty MedicineBologna University School of MedicineBolognaItaly