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WHO Classification of Tumours
Introduction: Histiocytic and dendritic cell neoplasms


Histiocytic neoplasms are derived from mononuclear phagocytes (macrophages and dendritic cells) or histiocytes. Dendritic cell tumours are related to several different lineages of accessory antigen-presenting cells (dendritic cells) that have a role in phagocytosis, processing and presentation of antigen to lymphoid cells.

Reticulohistiocytosis and Rosai-Dorfman disease, which are covered in the WHO Classification of Tumours of the Skin, will not be included in this chapter.

Epidemiology
Tumours of histiocytes are among the rarest of tumours affecting lymphoid tissues, probably representing less than 1% of tumours presenting in lymph nodes or soft tissues

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Favara BE, Feller AC, Pauli M, Jaffe ES, Weiss LM, Arico M, Bucsky P, Egeler RM, Elinder G, Gadner H, Gresik M, Henter JI, Imashuku S, Janka-Schaub G, Jaffe R, Ladisch S, Nezelof C, Pritchard J (1997)
Contemporary classification of histiocytic disorders. The WHO Committee On Histiocytic/Reticulum Cell Proliferations. Reclassification Working Group of the Histiocyte Society.
Med Pediatr Oncol 29: 157-66




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Pileri SA, Grogan TM, Harris NL, Banks P, Campo E, Chan JK, Favera RD, Delsol G, De Wolf-Peeters C, Falini B, Gascoyne RD, Gaulard P, Gatter KC, Isaacson PG, Jaffe ES, Kluin P, Knowles DM, Mason DY, Mori S, Müller-Hermelink HK, Piris MA, Ralfkiaer E, Stein H, Su IJ, Warnke RA, Weiss LM (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



. As several of these tumour types were poorly recognized until recently, their true incidence ­remains to be determined. Historically, some large cell lymphomas of B-cell or T-cell type were thought to be histiocytic or reticulum cell sarcomas on purely morpho­logical grounds, but only a small number prove to be of true macro­phage or dendritic cell origin. Some of the regulatory disorders such as macrophage activation or haemophagocytic syndromes may have large numbers of histiocytes but these are non-neoplastic. No sex, race or geographic predilection has yet been described (Table 14.01).

Histogenesis
The cellular counterparts of this group of neoplasms consist of myeloid-derived macrophages, myeloid-derived dendritic cells and stromal-derived dendritic cells. The myeloid-derived macrophages and dendritic cells constitute divergent lines of differentiation from bone marrow (BM) precursors, although transdifferentiation or hybrid differentiation states likely occur.

Monocytes, macrophages, histiocytes
Metchnikoff is considered the father of the macrophage and in 1883 coined the term "phagocytosis", postulating a central role for the process in the body’s innate defense against infection

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Gordon S (2007)
The macrophage: past, present and future.
Eur J Immunol 37 Suppl 1: S9-17




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Metchnikoff E (1883)
Untersuchungen uber die intracellulare Verdauung bei wirbellosen Thieren.
Arb Zoologischen Inst Univ Wien 5: 141



. The ­histiocytes/macrophages are derived from BM-derived monocytes and following ­migration/maturation in tissues participate in the innate response with pro- and anti-inflammatory cytokine effects as well as particulate removal and tissue reconstitution
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Gordon S (2007)
The macrophage: past, present and future.
Eur J Immunol 37 Suppl 1: S9-17




Click to access Pubmed
Gordon S, Taylor PR (2005)
Monocyte and macrophage heterogeneity.
Nat Rev Immunol 5: 953-64



. They are derived largely from the circulating peripheral blood (PB) monocyte pool that migrates through blood vessel walls to reach their site of action, but local proliferation also contributes
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Randolph GJ, Angeli V, Swartz MA (2005)
Dendritic-cell trafficking to lymph nodes through lymphatic vessels.
Nat Rev Immunol 5: 617-28



. Histiocytic tumours are closely related to the monocytic tumours from which their precursors are derived. The distinction between a leukaemic infiltrate of monocytic origin and histiocytic sarcoma can sometimes be difficult on morphologic grounds alone.

Macrophages display phagocytosis under some conditions of activation and, at this stage, there is heightened expression of lysosomal enzymes that can be demonstrated by histochemistry including non-specific esterases and acid phosphatase. Phagocytic activity is not a prominent feature of histiocytic malignancy but is a cardinal feature of the haemophagocytic syndromes. The haemophagocytic macro­phage activation syndromes are an important group of non-neoplastic proliferative disorders that need to be differentiated from true histiocytic neoplasms, and are far more common. The haemophagocytic syndromes are the result of genetic or ­acquired disorders in the regulation of macrophage activation. The primary familial lymphohistiocytic disorders are due to genetically determined inability to regulate macrophage killing by NK and/or T cells because of mutations in perforin, its packaging, export or release. Acquired or secondary causes of the haemophagocytic macrophage activation syndromes follow certain infections, most notably ­Epstein-Barr virus (EBV) and a wide variety of other infectious agents, as well as some malignancies, rheumatic disorders and multiple organ failure

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Janka GE (2007)
Hemophagocytic syndromes.
Blood Rev 21: 245-53



. The characteristic cytopenias of the haemophagocytic syndromes are most likely due to BM suppression by the cytokine storm since the BM is often hyper­cellular at the outset.

Myeloid-derived dendritic cells
Dendritic cells or antigen presenting cells are found in various sites and at different states of activation, and no single marker will identify all dendritic cell subsets

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Banchereau J, Briere F, Caux C, Davoust J, Lebecque S, Liu YJ, Pulendran B, Palucka K (2000)
Immunobiology of dendritic cells.
Annu Rev Immunol 18: 767-811




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Randolph GJ, Angeli V, Swartz MA (2005)
Dendritic-cell trafficking to lymph nodes through lymphatic vessels.
Nat Rev Immunol 5: 617-28




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Steinman RM, Hemmi H (2006)
Dendritic cells: translating innate to adaptive immunity.
Curr Top Microbiol Immunol 311: 17-58



. Langerhans cells (LC) are specialized dendritic cells in mucosal sites/skin that upon activation become specialized for antigen presentation to T cells, and then migrate to the lymph node through lymphatics. Lymph nodes also contain a paracortical dendritic cell type, the interdigitating cell (IDC) which may be derived in part from LC
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Geissmann F, Dieu-Nosjean MC, Dezutter C, Valladeau J, Kayal S, Leborgne M, Brousse N, Saeland S, Davoust J (2002)
Accumulation of immature Langerhans cells in human lymph nodes draining chronically inflamed skin.
J Exp Med 196: 417-30



. This classical dendritic cell lineage is believed to give rise to Langerhans cell histiocytosis/sarcoma and to IDC sarcoma. A third, poorly-defined DC subset, dermal/interstitial dendritic cells, are found in the soft tissue, dermis and in most organs, and can be increased in some inflammatory states
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Banchereau J, Briere F, Caux C, Davoust J, Lebecque S, Liu YJ, Pulendran B, Palucka K (2000)
Immunobiology of dendritic cells.
Annu Rev Immunol 18: 767-811



.
Plasmacytoid dendritic cells (PDC) (also known as plasmacytoid monocytes) are a distinct lineage of dendritic cells, which are believed to give rise to the blasticplasmacytoid dendritic cell neoplasm (See Chapter 6)

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Herling M, Jones D (2007)
CD4+/CD56+ hematodermic tumor: the features of an evolving entity and its relationship to dendritic cells.
Am J Clin Pathol 127: 687-700



. The histogenetic origins of PDC are controversial but are likely of myelomonocytic lineage. Interferon-α-producing PDC precursors, which are not strikingly dendritic in appearance, circulate in the PB and have the capacity to enter lymph nodes and tissue through high endothelial venules
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Liu YJ (2005)
IPC: professional type 1 interferon-producing cells and plasmacytoid dendritic cell precursors.
Annu Rev Immunol 23: 275-306



.

Stromal-derived dendritic cell types
Follicular dendritic cells (FDC), which are resident within primary and secondary B-cell follicles, trap and present antigen to B cells. FDC can store antigen on the cell surface as immune complexes for long periods of time

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van Nierop K, de Groot C (2002)
Human follicular dendritic cells: function, origin and development.
Semin Immunol 14: 251-7



. FDC appear to be closely related to BM stromal progenitors with features of myofibroblasts
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Maeda K, Matsuda M, Suzuki H, Saitoh HA (2002)
Immunohistochemical recognition of human follicular dendritic cells (FDCs) in routinely processed paraffin sections.
J Histochem Cytochem 50: 1475-86



. They are a non-migrating population that forms a stable meshwork within the follicle via cell-to-cell attachments and desmosomes.

Fibroblastic reticular cells (FRC) are involved in maintenance of lymphoid integrity, production and transport of cytokines and other mediators. In lymph nodes, they ensheath the post-capillary venules

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Katakai T, Hara T, Lee JH, Gonda H, Sugai M, Shimizu A (2004)
A novel reticular stromal structure in lymph node cortex: an immuno-platform for interactions among dendritic cells, T cells and B cells.
Int Immunol 16: 1133-42




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Vega F, Coombes KR, Thomazy VA, Patel K, Lang W, Jones D (2006)
Tissue-specific function of lymph node fibroblastic reticulum cells.
Pathobiology 73: 71-81



. They are of mesenchymal origin and express smooth muscle actin. Hyperplasia of FRC (i.e. stromal overgrowth) may be seen in Castleman’s disease
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Izumi M, Mochizuki M, Kuroda M, Iwaya K, Mukai K (2002)
Angiomyoid proliferative lesion: an unusual stroma-rich variant of Castleman's disease of hyaline-vascular type.
Virchows Arch 441: 400-5




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Lin O, Frizzera G (1997)
Angiomyoid and follicular dendritic cell proliferative lesions in Castleman's disease of hyaline-vascular type: a study of 10 cases.
Am J Surg Pathol 21: 1295-306



, and tumours of FRC arise in lymph nodes and have features of myofibroblastic tumours and closely related neoplasms
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Andriko JW, Kaldjian EP, Tsokos M, Abbondanzo SL, Jaffe ES (1998)
Reticulum cell neoplasms of lymph nodes: a clinicopathologic study of 11 cases with recognition of a new subtype derived from fibroblastic reticular cells.
Am J Surg Pathol 22: 1048-58



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Prognosis and predictive factors
Because there are few phenotypic markers unique for the dendritic or macrophage histiocytes, the investigator should use a panel appropriate to the cell in question and rigorously exclude other cell lineages (T cell, B cell, NK cell but also stromal, melanocytic and epithelial) by immuno­phenotypic and molecular means. It is also worth mentioning that some leukaemias and anaplastic large cell lymphoma can be accompanied in lymph nodes by an exuberant histiocytic response that may obscure the neoplastic cells.







Ronald Jaffe
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Ronald Jaffe
Department of Pathology
Children's Hospital
PA
USA




Stefano A. Pileri
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Stefano A. Pileri
Department of Haematology and Oncological Sciences
St Orsola - Malpighi Hospital, University of Bologna
Bologna
ITALY




Fabio Facchetti
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Fabio Facchetti
Department of Pathology
University of Brescia, Hospital of Brescia
Brescia
Italy




Daniel M. Jones
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Daniel M. Jones
Department of Pathology
U-T - M.D. Anderson Cancer Center
Houston
USA




Elaine S. Jaffe
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Elaine S. Jaffe
Laboratory of Pathology
National Cancer Institute, NIH
Bethesda
USA





Schematic diagram of the origin
Schematic diagram of the origin

Immunophenotypic markers of non-neoplastic macrophages and dendritic cells
Immunophenotypic markers of non-neoplastic macrophages and dendritic cells