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Blood Res (2024) 59:18

Published online May 7, 2024

https://doi.org/10.1007/s44313-024-00015-9

© The Korean Society of Hematology

Pathologic characteristics of histiocytic and dendritic cell neoplasms

Sun Och Yoon1*

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1Department of Pathology, Yonsei University College of Medicine, Severance Hospital, 50‑1 Yonsei‑Ro, Seodaemun‑Gu, Seoul 03722, South Korea

Correspondence to : *Sun Och Yoon
soyoon@yuhs.ac

Received: January 19, 2024; Accepted: April 5, 2024

Abstract

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Histiocytic and dendritic cell neoplasms comprise diverse tumors originating from the mononuclear phagocytic system, which includes monocytes, macrophages, and dendritic cells. The 5th edition of the World Health Organization (WHO) classification updating the categorization of these tumors, reflecting a deeper understanding of their pathogenesis.
In this updated classification system, tumors are categorized as Langerhans cell and other dendritic cell neoplasms, histiocyte/macrophage neoplasms, and plasmacytoid dendritic cell neoplasms. Follicular dendritic cell neoplasms are classified as mesenchymal dendritic cell neoplasms within the stroma-derived neoplasms of lymphoid tissues.
Each subtype of histiocytic and dendritic cell neoplasms exhibits distinct morphological characteristics. They also show a characteristic immunophenotypic profile marked by various markers such as CD1a, CD207/langerin, S100, CD68, CD163, CD4, CD123, CD21, CD23, CD35, and ALK, and hematolymphoid markers such as CD45 and CD43. In situ hybridization for EBV-encoded small RNA (EBER) identifies a particular subtype. Immunoprofiling plays a critical role in determining the cell of origin and identifying the specific subtype of tumors. There are frequent genomic alterations in these neoplasms, especially in the mitogen-activated protein kinase pathway, including BRAF (notably BRAF V600E), MAP2K1, KRAS, and NRAS mutations, and ALK gene translocation.
This review aims to offer a comprehensive and updated overview of histiocytic and dendritic cell neoplasms, focusing on their ontogeny, morphological aspects, immunophenotypic profiles, and molecular genetics. This comprehensive approach is essential for accurately differentiating and classifying neoplasms according to the updated WHO classification.

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Keywords: Mononuclear phagocyte system, Histiocytic and dendritic cell neoplasms, Histiocytosis, Immunophenotyping, Molecular genetics

Article

REVIEW

Blood Res 2024; 59():

Published online May 7, 2024 https://doi.org/10.1007/s44313-024-00015-9

Copyright © The Korean Society of Hematology.

Pathologic characteristics of histiocytic and dendritic cell neoplasms

Sun Och Yoon1*

1Department of Pathology, Yonsei University College of Medicine, Severance Hospital, 50‑1 Yonsei‑Ro, Seodaemun‑Gu, Seoul 03722, South Korea

Correspondence to:*Sun Och Yoon
soyoon@yuhs.ac

Received: January 19, 2024; Accepted: April 5, 2024

Abstract

Histiocytic and dendritic cell neoplasms comprise diverse tumors originating from the mononuclear phagocytic system, which includes monocytes, macrophages, and dendritic cells. The 5th edition of the World Health Organization (WHO) classification updating the categorization of these tumors, reflecting a deeper understanding of their pathogenesis.
In this updated classification system, tumors are categorized as Langerhans cell and other dendritic cell neoplasms, histiocyte/macrophage neoplasms, and plasmacytoid dendritic cell neoplasms. Follicular dendritic cell neoplasms are classified as mesenchymal dendritic cell neoplasms within the stroma-derived neoplasms of lymphoid tissues.
Each subtype of histiocytic and dendritic cell neoplasms exhibits distinct morphological characteristics. They also show a characteristic immunophenotypic profile marked by various markers such as CD1a, CD207/langerin, S100, CD68, CD163, CD4, CD123, CD21, CD23, CD35, and ALK, and hematolymphoid markers such as CD45 and CD43. In situ hybridization for EBV-encoded small RNA (EBER) identifies a particular subtype. Immunoprofiling plays a critical role in determining the cell of origin and identifying the specific subtype of tumors. There are frequent genomic alterations in these neoplasms, especially in the mitogen-activated protein kinase pathway, including BRAF (notably BRAF V600E), MAP2K1, KRAS, and NRAS mutations, and ALK gene translocation.
This review aims to offer a comprehensive and updated overview of histiocytic and dendritic cell neoplasms, focusing on their ontogeny, morphological aspects, immunophenotypic profiles, and molecular genetics. This comprehensive approach is essential for accurately differentiating and classifying neoplasms according to the updated WHO classification.

Keywords: Mononuclear phagocyte system, Histiocytic and dendritic cell neoplasms, Histiocytosis, Immunophenotyping, Molecular genetics

Fig 1.

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Figure 1.Overview of the origin and development of various cell types within the mononuclear phagocyte system, as well as those of stroma-derived/mesenchymal origin in lymphoid tissues, alongside their neoplastic counterparts. Abbreviations: BM, bone marrow; CMPs, common myeloid progenitors; CLPs, common lymphoid progenitors; GMPs, granulocyte–macrophage progenitors; cMoPs, common monocyte progenitors; CDPs, common dendritic cell progenitors; cDC, conventional dendritic cells; pDCs, plasmacytoid dendritic cells; moDC, monocyte-derived dendritic cell; JXG, juvenile xanthogranuloma; ECD, Erdheim-Chester disease; RDD, Rosai-Dorfman disease; ALK + H, ALK-positive histiocytosis; HS, histiocytic sarcoma; LCH, Langerhans cell histiocytosis; LCS, Langerhans cell sarcoma; IDDS, interdigitating dendritic cell sarcoma; IDDT, indeterminate dendritic cell tumor; MPDCP, mature plasmacytoid dendritic cell proliferation associated with myeloid neoplasm; BPDCN, blastic plasmacytoid dendritic cell neoplasm; SLO, secondary lymphoid organ; TLT, tertiary lymphoid tissue; FDC, follicular dendritic cell; FRC, fibroblastic reticular cell; FDCS, follicular dendritic cell sarcoma; EBV, Epstein Barr virus; FRCT, fibroblastic reticular cell tumor
Blood Research 2024; 59: https://doi.org/10.1007/s44313-024-00015-9

Fig 2.

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Figure 2.Tumor cells of LCH are round-to-oval histiocytes, with characteristic nuclear grooves and convolution, and prominent eosinophil infiltrates noted within the tumor microenvironment (A and B). In another LCH, tumor cells showing nuclear grooves are admixed with multinucleated giant cells of the osteoclast type, foamy histiocytes, and numerous small lymphocytes (C and D). In LCS, high-grade cytologic pleomorphism and confluent tumor necrosis are observed (E and F). In IDDS, the tumor cells appear as spindle to epithelioid cells, with a fascicular growth pattern, interspersed with small lymphocytes (G and H). LCH, Langerhans cell histiocytosis; LCS, Langerhans cell sarcoma; IDDS, interdigitating dendritic cell sarcoma
Blood Research 2024; 59: https://doi.org/10.1007/s44313-024-00015-9

Fig 3.

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Figure 3.JXG (A and B), noted as a well-circumscribed lesion (inset, B), consists of foamy histiocytes and Touton giant cells, mixed with lymphocytes. In ECD (C and D), a collection of foamy histiocytes intermingled with lymphocytes is observed. In RDD (E and F), prominent foamy histiocytes exhibiting emperipolesis are identified, accompanied by extensive plasma cell infiltration. At low magnification, the histiocytic clusters and lymphoplasmacytic tumor microenvironment create a contrasting light and dark pattern (inset, F). In ALK-positive histiocytosis (G and H), oval to spindle cells exhibit growth in fascicular and storiform patterns, interspersed with lymphocytes. Lastly, in HS (I-L), large pleomorphic tumor cells show high-grade cytologic atypia with increased mitosis and confluent tumor necrosis, displaying a storiform or whirling pattern that displaces the normal architecture of the lymph node. Abbreviations: JXG, juvenile xanthogranuloma; ECD, Erdheim-Chester disease; RDD, Rosai-Dorfman disease; HS, histiocytic sarcoma
Blood Research 2024; 59: https://doi.org/10.1007/s44313-024-00015-9

Fig 4.

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Figure 4.In BPDCN (A and B), immature blastic tumor cells infiltrate the dermis and subcutis, while sparing the epidermis. In FDCS (C and D), spindled and ovoid tumor cells, occasionally showing binucleation, grow in a fascicular pattern, interspersed with small lymphocytes. In EBV + FDSC, spindle-to-oval cells, resembling follicular dendritic cells, are either dispersed or form loose whorled fascicles, admixed with a rich and prominent lymphoplasmacytic infiltrate (E and F). Abbreviations: BPDCN, blastic plasmacytoid dendritic cell neoplasm; FDCS, follicular dendritic cell sarcoma; EBV, Epstein–Barr virus; EBV + FDCS, EBV-positive inflammatory follicular dendritic cell sarcoma
Blood Research 2024; 59: https://doi.org/10.1007/s44313-024-00015-9

Fig 5.

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Figure 5.Representative images of immunohistochemical expression in each subtype. Abbreviations: LCH, Langerhans cell histiocytosis; LCS, Langerhans cell sarcoma; IDDS, interdigitating dendritic cell sarcoma; ECD, Erdheim-Chester disease; RDD, Rosai-Dorfman disease; ALK + H, ALK-positive histiocytosis; HS, histiocytic sarcoma; BPDCN, blastic plasmacytoid dendritic cell neoplasm; FDCS, follicular dendritic cell sarcoma; EBV, Epstein Barr virus; EBV + FDCS, EBV-positive inflammatory follicular dendritic cell sarcoma
Blood Research 2024; 59: https://doi.org/10.1007/s44313-024-00015-9

Fig 6.

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Figure 6.Brief pathways affecting the pathogenesis of histiocytic and dendritic cell neoplasms. The MAPK pathway plays a pivotal role. Mutations in this pathway, especially the BRAF V600E mutation, are thought to originate from hematopoietic progenitors in the bone marrow, particularly in the pathogenesis of LCH and ECD. Additionally, gene mutations may occur in elements upstream of BRAF, such as RAS, or downstream, such as MAP2K1 (MEK1). Moreover, ALK gene translocation and CSF1R mutation, which affect the transmembrane RTK, can also be present in certain subtypes and are related to both MAPK and PI3K/AKT/mTOR pathways. The proliferation and accumulation of neoplastic histiocytes in tissues can lead to clinical symptoms such as inflammatory reactions, fibrosis, and tissue destruction. Abbreviations: RTK, receptor tyrosine kinase; BM, bone marrow; MAPK, mitogen-activated protein kinase; LCH, Langerhans cell histiocytosis; ECD, Erdheim-Chester disease
Blood Research 2024; 59: https://doi.org/10.1007/s44313-024-00015-9

Fig 7.

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Figure 7.Overall diagnostic process flow for the classification of histiocytic and dendritic cell neoplasms incorporates clinical presentations, morphology, immunohistochemistry, and molecular markers. Abbreviations: LC, Langerhans cell; XG, xanthogranuloma; IDDT, indeterminate dendritic cell tumor; LCH, Langerhans cell histiocytosis; JXG, juvenile xanthogranuloma; ECD, Erdheim-Chester disease; RDD, Rosai-Dorfman disease; IgG4-RD, IgG4-related disease; ALK + H, ALK-positive histiocytosis; IDDS, interdigitating dendritic cell sarcoma; HS, histiocytic sarcoma; LCS, Langerhans cell sarcoma; FDCS, follicular dendritic cell sarcoma; EBV, Epstein Barr virus; EBV + FDCS, EBV-positive inflammatory follicular dendritic cell sarcoma; FRCT, fibroblastic reticular cell tumor; BPDCN, blastic plasmacytoid dendritic cell neoplasm; HLM, hematolymphoid malignancies
Blood Research 2024; 59: https://doi.org/10.1007/s44313-024-00015-9

Overview of the characteristics of histiocytic and dendritic cell neoplasms.


Subtype (ICD-O coding, WHO 5th)HistomorphologyImmunophenotypeMolecular genetics
Langerhans cell and other dendritic cell neoplasms
Langerhans cell histiocytosis (9751/1; 9751/3)

Tumor cells: Large, round-to-oval histiocytes; nuclei ranging from grooved to convoluted; moderately abundant, eosinophilic cytoplasm; minimal atypia.

TME: Inflammatory infiltrates; prominent eosinophils; lymphocytes; multinucleated giant cells; fibrosis in advanced stages.

Positive expression.

: CD1a (membranous), S100 (nuclear and cytoplasmic), CD207/langerin (granular cytoplasmic), and CD68 (Golgi dot-like staining); S100 protein, CD163; BRAF V600E mutated protein (VE1).

Mutations in the MAPK pathway (~ 85%): BRAF V600E (50–60%), MAP2K1 (20%), BRAF, ARAF, NRAS, KRAS, HRAS
Langerhans cell sarcoma (9756/3)

Tumor cells: Pleomorphic histiocytes exhibiting high-grade cytology; large, atypical nuclei, clumped chromatin, high mitotic activity, frequent atypical mitoses, lacking nuclear grooves.

TME: Variable eosinophil infiltrates.

Positive expression: CD1a, S100, CD207/langerin (variable to focal expression)Limited information, Mutations in the MAPK pathway: KRAS, BRAF V600E (rare)
Indeterminate dendritic cell tumor (9757/3)

Tumor cells: Monomorphic, mononuclear cells resembling Langerhans cells; grooved nuclei, ample eosinophilic cytoplasm.

TME: A mixture of inflammatory cells including eosinophils and lymphocytes, reactive macrophages, multinucleated giant cells.

Positive expression: CD1a, S-100 protein.

Negative expression: CD207/langerin.

Limited information, BRAF V600E (rarely)
Interdigitating dendritic cell sarcoma (9757/3)

Tumor cells: Spindle-shaped to epithelioid cells; abundant cytoplasm, indistinct cell borders; occasional multinucleation, grooves, vesicular chromatin, distinct nucleoli; growth in sheets, fascicles, whorls, storiform pattern.

TME: Interspersed or aggregated small lymphocytes and plasma cells.

Positive expression: S-100 protein (highlighting dendritic cell processes); one or more hematolymphoid markers of such as CD45, CD4, CD43.

Negative expression:.

Langerhans cell markers (CD1a, CD207/langerin), follicular dendritic cell markers (CD21, CD23, CD35), other markers specific to certain neoplasms or melanoma.

Mutations in the MAPK pathway: BRAF V600E, KRAS, NRAS, MAP2K1
Histiocyte/Macrophage neoplasms
Juvenile xanthogranuloma (9749/1)

Tumor cells: Large, xanthomatous, foamy histiocytes, resembling dermal macrophages and lacking significant nuclear pleomorphism; growth in non-encapsulated, well-demarcated, and circumscribed pattern.

TME: Touton giant cells; a variable mixture of lymphocytes, eosinophils, plasma cells, neutrophils, and mast cells; fibrosis observed in regressed lesions.

Positive expression: CD68, CD163, CD4, CD14, factor XIIIa, fascin; S100 protein (occasionally).

Negative expression: CD1a, CD207langerin, ALK; BRAF-VE1(usually).

MAPK pathway: MAPK21, NRAS, KRAS, CSF1R mutations; BRAF fusion, NTRK1 fusion
Erdheim-Chester disease (9749/3)

Tumor cells: Bland, foamy, lipid-laden, and/ or small mononuclear histiocytes; occasionally, admixed with Langerhans cell histiocytosis.

TME: Touton giant cells, small lymphocytes, plasma cells, and/or neutrophils; fibrosis, which is sometimes prominent.

Positive expression: CD163, CD68, CD14, CD4, factor XIIIa, fascin; BRAF-VE1; S100 protein (rarely).

Negative expression: CD1a, CD207/langerin.

Mutations in the MAPK pathway: BRAF V600E (50–60%), ARAF, BRAF, NRAS, KRAS, MAP2K1; PIK3CA
Rosai-Dorfman disease (9749/3)

Tumor cells: Large histiocytes; round to oval vesicular nuclei, prominent nucleoli; abundant pale cytoplasm with indistinct borders; emperipolesis, a hallmark feature; minimal atypia; low mitotic activity; massive, marked sinus expansion pattern in the lymph node.

TME: Abundant polyclonal plasma cells, with occasional increases in IgG4-positive plasma cells; Lymphocytes and, less commonly, neutrophils; rare eosinophils; capsular and stromal fibrosis.

Positive expression; S100 (highlighting emperipolesis); OCT2, cyclinD1; macrophage markers (CD68, CD163); IgG4 (plasma cells).

Negative expression: CD1a, CD207/langerin, ALK, BRAF-VE1(usually).

Mutations in the MAPK/ERK pathway: KRAS, NRAS, MAP2K1, ARAF, CSF1R, BRAF V600E (rarely)
ALK-positive histiocytosis (9750/3)

Tumor cells: Large oval, foamy, and spindle cell histiocytes in variable proportions, lacking highgrade cytologic atypia; large histiocytes; irregularly folded nuclei, fine chromatin, abundant eosinophilic cytoplasm, with occasional minor emperipolesis; foamy histiocytes showing vacuolated cytoplasm and irregularly folded nuclei, sometimes accompanied by Touton giant cells; spindle histiocytes exhibiting a fascicular or storiform growth pattern, elongated nuclei, and eosinophilic cytoplasm.

TME: Comprised of small lymphocytes and plasma cells.

Positive expression: ALK (cytoplasmic, rarely membranous or Golgi dot pattern; never in nuclear pattern); at least two histiocytic markers (CD163, CD68, CD14, CD4, lysozyme); occasionally S100 protein, cyclinD1, OCT2.

Negative expression: CD1a, CD207/langerin, CD30, BRAF-VE1.

ALK::KIF5B (most common); CLTC-ALK, TPM3-ALK, TFG-ALK, EML4-ALK, and DCTN1-ALK
Histiocytic sarcoma (9755/3)

Tumor cells: Non-cohesive, large with abundant eosinophilic cytoplasm; variably pleomorphic, grooved, or irregularly folded nuclei, distinct nucleoli; prominent mitotic activity, atypical mitoses; diffuse sheets, sinusoidal distribution.

TME: Reactive inflammatory and stromal cells admixture.

Positive expression: two or more histiocytic markers (CD163, CD68, lysozyme); CD4, CD45; S100 protein (usually patch).

Negative expression: Langerhans cell markers (CD1a, CD207/langerin), follicular dendritic cell markers (CD21, CD23, CD35), myeloid cell markers (myeloperoxidase, CD13); ALK; melanocytic markers (SOX10, HMB-45); epithelial markers (cytokeratins); and other specific markers for certain neoplasms, including hematopoietic tumors.

Mutations in the MAPK pathway: KRAS, BRAF V600E, NRAS, MAP2K1, and CSF1R
Plasmacytoid dendritic cell neoplasms
Mature plasmacytoid dendritic cell proliferation associated with myeloid neoplasm (no code)

Tumor cells: Medium-sized, mature plasmacytoid cells; round or oval nuclei, moderate amphophilic cytoplasm; absence of mitotic figures; aggregation or interstitial scattering in bone marrow.

TME: Associated with underlying myeloid neoplasm.

Positive expression: CD123; other pDC markers such as TCF4, TCL1, CD303, CD304 with possible aberrant loss; CD34, TdT, CD56 (absent, low, or partial expression)Depends on associated myeloid neoplasm
Blastic plasmacytoid dendritic cell neoplasm (9727/3)Tumor cells: Medium-sized, immature, and blastic, resembling lymphoblasts or myeloblasts; scanty cytoplasm, eccentrically positioned round or irregular nuclei, fine chromatin, and one to several inconspicuous nucleoli; presence of variable mitotic figures and necrosis

Immunophenotypic diagnostic criteria:.

1. Mandatory expression of CD123 along with at least one other pDC marker (such as TCF4, TCL1, CD303, or CD304), in addition to either CD4 and/or CD56 Or.

2. Expression of any three pDC markers (including CD123, TCF4, TCL1, CD303, CD304), along with the absence of all expected negative markers of lymphoid or myeloid lineage (such as CD3, CD14, CD19, CD34, lysozyme, and myeloperoxidase).

NF-κB pathway
Mesenchymal dendritic cell neoplasms of lymphoid tissues: Follicular dendritic cell neoplasmsa
Follicular dendritic cell sarcoma (9758/3)

Tumor cells: Spindled, ovoid, or epithelioid shape with moderate eosinophilic cytoplasm, indistinct cell borders; elongated nuclei with vesicular chromatin, thin nuclear membranes, distinct nucleoli, intranuclear pseudoinclusions, occasional binucleation; occasional prominent cytologic atypia; growth patterns in whorls, fascicles, syncytial sheets, storiform pattern.

TME: Interspersed small lymphocytes and plasma cells within the tumor or forming aggregates.

Positive expression: Two or more FDC markers including CD21, CD23, CD35, clusterin, CXCL13, D2-40 (podoplanin).

Negative expression: S100 protein; other specific markers for certain hematolymphoid neoplasms.

Limited information, NF-kB pathway, BRAF V600E
EBV-positive inflammatory follicular dendritic cell sarcoma (9758/3)

Tumor cells: Spindle to oval shape with indistinct borders; scant to moderate cytoplasm; vesicular nuclei with small, distinct nucleoli; occasional binucleation; variable nuclear atypia and cellular pleomorphism; rare mitotic figures, often with necrosis and hemorrhage; growth in dispersed or loosely whorled fascicle patterns.

TME: Prominent lymphoplasmacytic infiltrate.

Positive expression: FDC markers (CD21, CD23, CD35, CXCL13, D2-40); rarely, fibroblastic/myoid markers (SMA); EBV-encoded small RNA (EBER)Limited information
Fibroblastic reticular cell tumor (9759/3)

Tumor cells: Spindle to ovoid shape with indistinct cell borders and vesicular nuclei; growth patterns in whorls, fascicles, or sheets; variable nuclear pleomorphism; overlapping morphological features with follicular dendritic cell sarcoma and interdigitating dendritic cell sarcoma; presence of intercellular collagen fibrils.

TME: interspersed with small lymphocytes.

Positive expression: one of more of the following markers (cytokeratin, actin, desmin, with delicate cell processes pattern).

Negative expression: FDC markers (CD21, CD23, CD35, CXCL13); interdigitating dendritic cell markers (S100).

Limited information

a Follicular dendritic cell neoplasms are classified as mesenchymal dendritic cell neoplasms within the stroma-derived neoplasms of lymphoid tissues rather than histiocytic and dendritic cell neoplasms in the 5th WHO classification.

References are displayed in the main text section.

Abbreviations: FDC, follicular dendritic cell; TME, tumor microenvironment.
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