Lymph nodes & spleen, nonlymphoid
Neoplasms (not lymphoma)
Langerhans cell histiocytosis


Topic Completed: 2 March 2020

Revised: 5 March 2020

Copyright: 2003-2020, PathologyOutlines.com, Inc.

PubMed Search: Langerhans cell histiocytosis[TI] lymph node[TIAB]

See Also: Bone and Lung tumor chapters

Vignesh Shanmugam, M.D.
Olga Pozdnyakova, M.D., Ph.D.
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Cite this page: Shanmugam V, Pozdnyakova O. Langerhans cell histiocytosis. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/lymphnodesLCH.html. Accessed April 3rd, 2020.
Definition / general
  • Langerhans cell histiocytosis (LCH) is a clonal proliferation of cells that morphologically and immunophenotypically resemble Langerhans cells
Essential features
  • Langerhans cell histiocytosis is a clonal proliferation of cells that morphologically and immunophenotypically resemble Langerhans cells
  • More common in childhood (1 - 3 years old) and involves nodal and extranodal sites (most common site is bone)
  • Lesional cells show prominent nuclear grooves with admixed eosinophils and are positive for CD1a, langerin (CD207) and S100
  • Most cases harbor BRAF V600E mutations and other RAS / MAPK pathway activating mutations (Blood 2010;116:1919)
  • Unifocal disease is generally associated with a good prognosis, whereas multisystem and multifocal disease is associated with poor prognosis
Terminology
  • Histiocytosis X
  • Eosinophilic granuloma (solitary bone lesion)
  • Hand-Schüller-Christian disease (multiple lesions)
  • Hashimoto-Pritzker disease
  • Letterer-Siwe disease (disseminated or visceral involvement)
ICD coding
  • ICD-10: C96.0 - multifocal and multisystemic (disseminated) Langerhans cell histiocytosis
  • ICD-10: C96.5 - multifocal and unisystemic Langerhans cell histiocytosis
  • ICD-10: C96.6 - unifocal Langerhans cell histiocytosis
  • ICD-O: 9751/3 - Langerhans cell histiocytosis, NOS
Epidemiology
  • More common in childhood (1 - 3 years old)
  • Incidence: 3 - 5 per million children, 1 - 2 per million adults (Blood 2015;126:26)
  • M > F
  • Pulmonary Langerhans cell histiocytosis strongly associated with smoking
Sites
  • Can be unifocal, multifocal but involving a single organ system or involve multiple organs (Blood 2015;126:26)
  • The most common sites involved are bone and adjacent soft tissue
  • The following sites can also be involved, particularly in multisystem disease (in order of decreasing frequency): bone, skin, bone marrow, lymph nodes, liver, spleen, oral mucosa, lung, central nervous system / pituitary and gastrointestinal tract
  • Brain involvement can result in a neurodegenerative syndrome; pituitary involvement can present with diabetes insipidus (Brain 2005;128:829)
Pathophysiology
  • The majority of cases are clonal and harbor driver mutations involving the RAS / MAPK pathway (Blood 2010;116:1919)
  • Misguided myeloid / dendritic cell model
    • Clinical severity and distribution of Langerhans cell histiocytosis lesion(s) may be defined by the cellular stage of myeloid differentiation during which the somatic BRAF V600E or other activating kinase mutation arises and results in pathological extracellular signal regulated kinases (ERK) activation (Br J Haematol 2015;169:3)
Etiology
  • Pulmonary Langerhans cell histiocytosis is strongly associated with smoking (N Engl J Med 2002;346:484)
  • Causes for other forms are unknown
Diagrams / tables

Contributed by Vignesh Shanmugam, M.D.

Misguided myeloid / dendritic cell model

Diagnosis
  • Imaging studies (Blood 2015;126:26):
    • Skeletal survey
    • PET-CT scan
    • MRI: most effective for brain lesions
  • Bone marrow biopsy / aspiration in patients with cytopenias
  • Endoscopy to rule out gastrointestinal involvement in patients with evidence of malabsorption
  • Biopsy of lesion(s): complete excision is not required, particularly for bone lesions
Laboratory
  • Complete blood count: cytopenias suggest bone marrow involvement (Blood 2015;126:26)
  • Liver function studies: abnormal if liver involved
Radiology description
Radiology images

Contributed by Vignesh Shanmugam, M.D.

Sagittal view

Coronal view



Images hosted on other servers:

LCH

Prognostic factors
  • Localized (single system) disease: good outcome
  • Multiorgan (2 or more organs) or multisystem disease including liver, spleen or bone marrow: poor outcome (Blood 2015;126:26)
Case reports
Treatment
  • Surgical resection may be sufficient for single system disease (Blood 2015;126:26)
    • Curettage may be sufficient for isolated bone lesions
  • Systemic chemotherapy (vinblastine, prednisone, mercaptopurine)
  • Smoking cessation for pulmonary Langerhans cell histiocytosis
Microscopic (histologic) description
  • Partial effacement of lymph node with preservation of follicular centers
  • Infiltration of sinuses by Langerhans cells: 12 - 15 microns in diameter with abundant, pale eosinophilic cytoplasm, irregular and elongated nuclei with prominent nuclear grooves and folds, fine chromatin and indistinct nucleoli (Arch Pathol Lab Med 2015;139:1211)
  • Occasionally multinucleated
  • Sinuses commonly have foci of necrosis, often surrounded by rim of eosinophils
  • Variable mitotic activity
Microscopic (histologic) images

Contributed by Vignesh Shanmugam, M.D.

Preservation of follicle centers

Sinusoidal infiltration

Infiltrate of subcapsular sinus

Frequent admixed eosinophils

Prominent nuclear grooves


Admixed multinucleated giant cells

Langerin

CD1a

S100

Cyclin D1



AFIP images


With Hodgkin lymphoma

Involving spleen

Malignant

S100

Nuclear and cytoplasmic staining S100



Case #314

Diffuse involvement

Sinusoidal and pericapsular involvement

Pericapsular involvement


Admixed eosinophils

Nuclear grooves

Mitotic activity


CD1a

CD5

CD20

CD23

Langerin

S100

Cytology images

Contributed by Vignesh Shanmugam, M.D.

Prominent nuclear grooves and admixed eosinophils

Scattered multinucleated giant cells

Negative stains
Electron microscopy description
  • Birbeck granules: tennis racquet shaped, 200 - 400 nm long and 33 nm wide, with a zipper-like appearance (Mol Biol Cell 2002;13:317)
Electron microscopy images

AFIP images

Birbeck granules



Images hosted on other servers:

Birbeck granules

Molecular / cytogenetics description
Sample pathology report
  • Lymph node, right inguinal, excisional biopsy:
    • Langerhans cell histiocytosis (see comment)
    • Comment: The sections show lymph node tissue with an infiltrate of epithelioid cells involving the interfollicular areas and sinuses. The infiltrate is composed of cells with irregular to folded nuclei with prominent nuclear grooves, vesicular chromatin, distinct nucleoli and moderate amounts of pale eosinophilic cytoplasm. Frequent admixed eosinophils are seen. Reactive appearing germinal centers are relatively preserved.
    • Immunohistochemical studies demonstrate that the lesional cells are strongly positive for CD1a, langerin, S100 and cyclin D1.
Differential diagnosis
Board review style question #1
Which of the following is the most frequently mutated gene in the entity pictured below?



  1. ARAF
  2. BRAF
  3. KRAS
  4. MAP2K1
  5. NRAS
Board review answer #1
B. BRAF. The image shows histiocytoid cells in a background of eosinophils and multinucleated cells characteristic of Langerhans cell histiocytosis. The most frequent driver mutation in Langerhans cell histiocytosis is the BRAF V600E mutation (50% of cases).

Comment Here

Reference: Langerhans cell histiocytosis
Board review style question #2
A 2 year old boy presents with generalized lymphadenopathy, hepatosplenomegaly and lytic bone lesions. A diagnostic lymph node biopsy is performed which shows a sinusoidal infiltrate. Electron microscopy reveals club shaped structures in the lesional cells. Which of the following clinical findings can be seen in this entity?

  1. Bilateral sclerotic long bone lesions
  2. Elevated white blood cell count
  3. Hairy kidney
  4. Neurodegeneration
  5. Serum monoclonal paraprotein
Board review answer #2
D. Neurodegeneration. The clinical scenario describes an aggressive presentation of multisystem Langerhans cell histiocytosis in a young patient. The histologic findings are characterized by sinusoidal involvement and electron microscopy shows Birbeck granules, i.e. club shaped or tennis racquet shaped structures in the neoplastic Langerhans cells. Brain involvement by Langerhans cell histiocytosis can result in neurodegenerative syndrome or diabetes insipidus secondary to involvement of the hypothalamic pituitary axis. Hairy kidney and sclerotic bone lesions are characteristic of Erdheim-Chester disease. Serum monoclonal paraproteins are typically seen in association with B cell lymphomas and plasma cell neoplasms.

Comment Here

Reference: Langerhans cell histiocytosis
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