Chapter 7 – Malignant Disorders of the Histiocytic/Dendritic Lineage




Abstract




Disorders of histiocytic and dendritic cell origin, traditionally referred to as histiocytoses [1], form a group of extremely rare tumours, characterized by variable malignant potential and unpredictable clinical course, from spontaneously regressing to rapidly progressing. While the neoplastic character of some of these entities is still debated, the most commonly acknowledged predictors of malignant behaviour remain as morphological features, i.e. degree of cellular anaplasia. Some of these disorders show predilection for skeletal involvement (Langerhans cell histiocytosis, LCH; Erdheim–Chester disease, ECD) but bone marrow (BM) infiltration is infrequent. In turn, entities classified as frankly malignant (e.g. histiocytic sarcoma, HS) most often form tumoural masses in lymph nodes or at extranodal sites. Interestingly, many of the tumoural lesions in this category demonstrate ability to transdifferentiate to and from other malignancies, including lymphomas and leukaemias. Therefore although primary histiocytic or dendritic cell disorders are most commonly diagnosed in skeletal, soft tissue or lymph node biopsies, BM biopsies (BMB) and aspirates may be obtained for staging purposes or in cases when occurrence of secondary malignancy is suspected.





Chapter 7 Malignant Disorders of the Histiocytic/Dendritic Lineage



Monika Klimkowska



Introduction


Disorders of histiocytic and dendritic cell origin, traditionally referred to as histiocytoses [1], form a group of extremely rare tumours, characterized by variable malignant potential and unpredictable clinical course, from spontaneously regressing to rapidly progressing. While the neoplastic character of some of these entities is still debated, the most commonly acknowledged predictors of malignant behaviour remain as morphological features, i.e. degree of cellular anaplasia. Some of these disorders show predilection for skeletal involvement (Langerhans cell histiocytosis, LCH; Erdheim–Chester disease, ECD) but bone marrow (BM) infiltration is infrequent. In turn, entities classified as frankly malignant (e.g. histiocytic sarcoma, HS) most often form tumoural masses in lymph nodes or at extranodal sites. Interestingly, many of the tumoural lesions in this category demonstrate ability to transdifferentiate to and from other malignancies, including lymphomas and leukaemias. Therefore although primary histiocytic or dendritic cell disorders are most commonly diagnosed in skeletal, soft tissue or lymph node biopsies, BM biopsies (BMB) and aspirates may be obtained for staging purposes or in cases when occurrence of secondary malignancy is suspected.



Cell of Origin Classification


The currently accepted definition of the mononuclear phagocyte system (MPS) was first proposed in 1969 [2] but is constantly evolving [3]. The MPS is responsible for innate immune responses and consists of monocytes circulating in peripheral blood, macrophages or tissue-residing histiocytes and dendritic cells (DCs). Monocytes and macrophages originate from haematopoietic precursors in BM, participate in both acute and chronic phase of inflammation [4], and can differentiate into other MPS cell types. Dendritic cells remain the subjects of intensive studies but their development seems not to be fully understood yet. They may originate from embryonic precursors (dermal and mucosal Langerhans cells, LCs) or from common DC precursor (CDP) found in BM, developing through circulating precursors (pre-DC) [5]. From marrow CDPs originate both plasmacytoid DCs and other DC subsets found in lymphatic tissue and other organs, including the so-called mesenchymal- or stromal-derived DCs.


The MPS cells are dynamic and may demonstrate overlapping morphological or phenotypical features. In the tumoural context, disorders of BM precursor origin include LCH, Langerhans cell sarcoma (LCS), ECD, HS and interdigitating dendritic cell sarcoma (IDCS). Tumours of mesenchymal- or stromal-derived DC origin include follicular dendritic cell sarcoma (FDCS), indeterminate dendritic cell sarcoma (INDCS), disseminated juvenile xanthogranuloma (DXG, systemic counterpart of juvenile xanthogranuloma, JXG), and fibroblastic reticular cell tumour (FRCT). From the morphological perspective, histiocytic infiltrates are prominent in ECD, DXG and HS, whereas transformed oval or spindle-shaped DCs dominate the picture in the remaining entities.


In the recent classification by the World Health Organization (WHO) [1], all the above-mentioned disorders are grouped under the category of ‘Histiocytic and Dendritic Cell Neoplasms’ (Table 7.1). However, the Histiocyte Society proposed a revised classification involving both morphological, phenotypical and molecular features as well as clinical presentation and radiological findings (Table 7.2) [6]. Several of these entities were discussed in Chapter 6 (ECD, Rosai–Dorfman disease (RDD) and haemophagocytic lymphohistiocytosis (HLH)) and the remainder will be addressed below and summarized in Table 7.3.




Table 7.1 Classifications of histiocytic and dendritic cell neoplasms according to WHO 2017 [1].












































Neoplasm Malignant potential
Histiocyte derived Erdheim–Chester disease (ECD) Variable, mostly chronic disease
Xanthogranuloma family (juvenile XG, disseminated XG, adult XG) Benign, systemic variant more aggressive
Histiocytic sarcoma (HS) Malignant, poor prognosis
Dendritic cell derived Langerhans cell histiocytosis (LCH) Variable
Langerhans cell sarcoma (LCS) Malignant, poor prognosis
Interdigitating dendritic cell sarcoma (IDCS) Malignant, poor prognosis
Indeterminate dendritic cell sarcoma (INDCS) Malignant, variable course
Follicular dendritic cell sarcoma (FDCS) Malignant, good prognosis



Table 7.2 Classification of histiocytoses according to Histiocyte Society 2016 [6].








































Tumour group Clinical features Most common entities
L Group Variable clinical presentation

Skeletal involvement common

Endocrinological and/neurodegenerative complications possible
Langerhans cell histiocytosis
Erdheim–Chester disease
Disseminated juvenile xanthogranuloma
C Group Mucosal and/or dermal lesions Xanthogranuloma family
Benign cephalic histiocytosis
Multicentric reticulohistiocytosis, cutaneous RDD
R Group Classical presentation with lymphadenopathy and systemic symptoms

Extranodal involvement in 43% cases

Association with ALPS and Autoimmune Lymphoproliferative Syndrome IgG4 disease
Rosai–Dorfman disease family
M Group Frankly malignant

Nodal or extranodal masses

Association with other haematological malignancies
Histiocytic sarcoma

Interdigitating dendritic cell sarcoma

Indeterminate dendritic cell sarcoma

Langerhans cell sarcoma

(Follicular dendritic cell sarcoma excluded)
H Group Systemic hyperinflammatory syndrome

Primary FHL and Familial Hemophagocytic Lymphohistiocytosis, due to inherited mutations

Secondary, most commonly due to infection, autoimmunity, malignancy
Haemophagocytic lymphohistiocytosis

Macrophage activation syndromes



Table 7.3 Clinical and pathological characteristics of main histiocytic and dendritic cell disorders.










































































Type of tumour Tumour cell morphology Inflammatory component Immunophenotype Clinical presentation Association with other malignancies
Erdheim–Chester disease (ECD) Single or multinucleated histiocytes

Foamy transformed cells
+/++

Prominent fibrosis
CD14+

CD68+

CD163+

FXIIIa+

Fascin+

CD1a–

S100–

Langerin–
Multisystem disease

Skeletal involvement >95% cases

Retroperitoneal, perinephric and paraaortic fibrosis (DD: IgG4-related disease)
LCH (may coexist in the same lesion)
Xanthogranuloma family (juvenile XG, disseminated XG, adult XG) Small oval to spindle-shaped histiocytes

Xanthomatous cells

Occasional Touton cells
+/++ CD14+

CD68+

CD163+

FXIIIa+

Fascin+

CD1a–

S100–

Langerin–
Mostly cutaneous (head and neck region) and mucosal lesions

Systemic involvement may include CNS and BM
LCH

Juvenile myelomonocytic leukaemia (in the context of neurofibromatosis type 1)
Histiocytic sarcoma (HS) Large round to oval cells

Areas of spindling

Mild to prominent atypia

Haemophagocytosis
+/++ CD14+

CD68+

CD163+

Lysozyme+

HLA-DR+

CD1a–

S100–/+

Langerin–
Single lesion with systemic symptoms

or: multifocal disease with engagement of intestines and BM
Clonally related NHL or ALL

AML
Langerhans cell histiocytosis (LCH) Oval middle-sized cells with indented, folded or grooved nuclei

Eosinophilic cytoplasm

Minimal atypia
+++

Eosinophilic abscesses with central necrosis and Charcot–Leyden crystals
CD1a+

S100+

Langerin+

CD68+

HLA–DR+

PDL1+

Cyclin D1+
Mostly skin, bone and LN involvement:

– single system (multifocal or single lesion);

– multisystem (visceral)

Risk organs: BM, liver, spleen

Lung lesions in adults smoking-related
ECD

Hairy cell leukaemia

Malignant melanoma
Langerhans cell sarcoma (LCS) LCH-like but with prominent nuclear pleomorphism and atypia + CD1a+

S100+

Langerin+

CD68+

HLA–DR+
Mostly extranodal multifocal tumours Leukaemias (AML, ALL, CLL, CML)

Myelodysplastic syndrome

Non-Hodgkin lymphoma
Interdigitating dendritic cell sarcoma (IDCS) Spindle cells, storiform or fascicular pattern

Eosinophilic cytoplasm

Mild atypia

Paracortical distribution
+/++ S100+

CD1a–

Langerin–

Fascin+

CD68+

CD4+

Lysozyme+

(p53+)
Asymptomatic LN mass Non-Hodgkin lymphoma

AML
Indeterminate dendritic cell sarcoma (INDCS) LC-like

Multinucleated cells

Eosinophilic cytoplasm
S100+

CD1a+

Langerin–

Fascin+

CD163–

CD68+/–

CD4+/–

Lysozyme+/–
Skin lesions

Lymphadenopathy rare
Non-Hodgkin lymphoma
Follicular dendritic cell sarcoma (FDCS) Spindled to ovoid cells

Nuclear pseudoinclusions

Multinucleated cells

Storiform or fascicular pattern, sheets or nodules
+/– CD21+

CD23+

CD35+

Fascin+

CXCL13+

CD4+

Clusterin+

CD1a–

S100–

Langerin–
Slow-growing asymptomatic mass

Nodal (neck) or extranodal sites (GI tract, liver, spleen, mediastinum, soft tissue)
? (questionable FDC proliferations in angioimmunoblastic lymphomas described)

The field of histiocytic and dendritic cell disorders is undergoing constant evolution and attracts a lot of scientific attention. It should be noted, though, that of all haematopoietic diseases of neoplastic character, histiocytoses are the rarest and the most elusive. The crude incidence rate of malignant histiocytic and DC tumours in European countries was 0.053 × 100,000/year in 2007, with estimated 278 new cases in 2013 [7].



Phenotypic Features


It is generally recognized that monocytic/histiocytic tumours are composed of cytoplasm-rich ovoid cells, whereas DC lesions have a more stellate cell appearance. In both groups spindle cells may be a prominent feature and a variable amount of a non-neoplastic inflammatory component, including plasma cells, small lymphocytes, eosinophils and reactive histiocytes, may be found. The tumour cell component itself may be low, e.g. in LCH it may account for only 8% of the entire infiltrate [8].


Histiocytic tumours may show prominent vacuolization, at times resembling foamy macrophages or storage cells (Figure 7.1). Lipid accumulation may also be a prominent feature, such as in JXG or ECD. Giant or multinucleated forms, including Touton cells, may be numerous, and fibrosis is usually seen in ECD. Infiltrates in tissue samples may remind one of mast cell aggregates.


Jan 4, 2021 | Posted by in HEMATOLOGY | Comments Off on Chapter 7 – Malignant Disorders of the Histiocytic/Dendritic Lineage
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