Non-Langerhans Cell Histiocytoses

Non-Langerhans Cell Histiocytoses

Aaron Auerbach, MD, PhD

Indeterminate cell histiocytosis is a very rare histiocytosis composed of cells with histologic and immunohistochemical similarities to Langerhans cells, but lacking Birbeck granules by electron microscopy.

Hereditary progressive mucinous histiocytosis shows a dermal proliferation composed of epithelioid histiocytes image and mucin separating broad bundles of collagen image.



  • Non-X histiocytoses


  • Wide range of histiocytic disorders that are not derived from Langerhans cells

    • Sometimes difficult to categorize because of overlapping morphologic and clinical findings

    • Includes juvenile xanthogranuloma, reticulohistiocytoma, and Rosai-Dorfman disease

  • Histiocyte = bone marrow-derived cell belonging to monocytes/macrophage &/or dendritic cell lineage and functional variants

    • Includes macrophages, Langerhans cells, interstitial dendritic cells, interdigitating dendritic cells, plasmacytoid dendritic cells, microglia, Kupffer cells, and alveolar macrophages



  • Age

    • Depends on type of histiocytosis


  • Benign tumors that do not require treatment in most cases


  • Depends on type of histiocytosis


Histologic Features

  • Macrophages are large (15-25 µm in diameter) phagocytic cells with irregular shapes and pseudopodia

    • Nucleus is round, but may be indented or reniform

    • Nuclear membrane is indistinct, and chromatin is fine

    • Cytoplasm is abundant and can be granulated

    • Cytoplasmic vacuoles may be seen, and phagocytosed material may be present

  • Other features depend on the type of histiocytosis



  • Depends on type of histiocytosis

    • Macrophages are typically positive for CD14, CD68, and CD163

    • Dermal/interstitial dendritic cells are positive for FXIIIA, CD14, CD163, and fascin

    • Indeterminate cells are S100(+), CD1a(+), FXIIIA(+)

Electron Microscopy

  • Non-Langerhans cell histiocytoses do not have Birbeck granules by ultrastructural studies, unlike Langerhans cell histiocytosis (LCH)


Benign Cephalic Histiocytosis

  • Rare histiocytosis characterized by asymptomatic, self-healing reddish to brownish macules and papules on the head, which spread later to trunk and arms

    • Begins in children ≤ 3 years old

  • Morphology

    • Dermal histiocytes, fairly small with round nuclei

      • ± vacuolated cytoplasm

      • Positive for CD68, CD11a, and CD11c; negative for S100 and CD1a

    • Patterns include papillary dermal, lichenoid, and diffuse

      • Usually no epidermotropism

  • Electron microscopy shows comma-shaped bodies, coated vesicles, and desmosome-like structures with absence of Birbeck granules

Generalized Eruptive Histiocytoma

  • Rare benign histiocytosis characterized by crops of hundreds of blue-red papules, affecting mainly adults, and self-healing

    • Symmetrically distributed on trunk and extremities

      • May become hyperpigmented macules when they regress

  • Clinical course

    • Usually self-limiting; may last from 1 month to over 12 years

      • May persist, may resolve, or may relapse

    • Sometimes associated with underlying tumors

      • Macules/papules may regress when underlying malignancy is treated

  • Morphology

    • Histiocytes in upper dermis

      • Sometimes small and vacuolated cytoplasm

      • ± perivascular distribution

    • Usually no multinucleated giant cells

    • Older lesions may show fibrosis or giant cells

    • CD68(+), S100(-), CD1a(-)

  • Electron microscopy shows dense bodies with myelin, but no Birbeck granules

Indeterminate Cell Histiocytosis (ICH)

  • Dendritic cells in dermis with features of histiocytes and Langerhans cells but no Birbeck granules

    • Only few cases reported

  • Presentation

    • Numerous red/brown papules

      • May coalesce

  • Morphology

    • Monomorphous infiltrate of mononuclear histiocytes intermixed with clusters of lymphocytes

      • Rarely multinucleated cells

      • Often increased numbers of reactive T cells interspersed among histiocytic cells

      • Usually ample pale cytoplasm and clefted nuclei

      • Rare spindle cell variant has been described

      • Stroma can be myxoid

    • Immunohistochemistry

      • S100(+), CD68(+), CD1a(+), FXIIIA(±)

  • Sometimes look like Langerhans cells with ample cytoplasm and grooves

    • But lack some Langerhans markers such as Langerin and Birbeck granules

Progressive Nodular Histiocytosis

Jul 8, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Non-Langerhans Cell Histiocytoses
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