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Langerhans cell histiocytosis

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Cite this page: Magliocca K, Martinez A. Langerhans cell histiocytosis. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/mandiblemaxillaLCH.html. Accessed March 26th, 2023.

Definition / general

Clonal proliferation of Langerhans cells (immature dendritic cells)
The World Health Organization classification of hematopoietic and lymphoid tumors classifies Langerhan cell histiocytosis (LCH) as a dendritic cells disorder
- This grouping includes Langerhans cell histiocytosis, secondary dendritic cell processes, juvenile xanthogranuloma, solitary histiocytomas with a dendritic phenotype and Erdheim-Chester disease

Essential features

Clonal proliferation of reniform or cleaved histiocytes with eosinophils
Langerhans histiocytes are positive for CD1a and show Birbeck granules by EM
- Vermiform bodies are characteristic of congenital self healing LCH
Treatment and prognosis based on single or multisystem involvement

Terminology

Langerhans cell histiocytosis (LCH)
Eosinophilic granuloma (EG)
Histiocytosis X
- Encompasses all terminology including Letter-Siwe syndrome and Hand-Schuller-Christian disease
Congential self healing LCH
- Important special subtype of LCH to recognize because of spontaneously resolution
  - Unique ultrastructural features (see Electron microscopy description below)

Epidemiology

The incidence appears to be 3 - 5 cases per million children and 1 - 2 cases per million adults
Primarily affects individuals in the first three decades
- 80% are diagnosed in patients younger than 30 years
- 50% are diagnosed in patents younger than 10 years
Peak incidence is 1 - 4 year of age

Sites

Bone is the most common site of involvement (77%)
Craniofacial bones are most frequently affected
- Jaws are involved in 30% of adults and ~10% of children
  - Skull lesions are more common in children
- Jaws involvement is 2× more common than the oral soft tissues
  - Mandible 3× more common than maxilla

Etiology

Clonal population of immature dendritic cells
- This is in contrast to normal, mature Langerhans cells
- LCH cells tend to lose ability to present antigen but still secrete cytokines that function in lesion establishment and persistence

Clinical features

Most common intraoral signs and symptoms at presentation include an intraoral mass, pain, gingivitis and loose teeth
Diabetes insipidus, exophthalmos and hepatosplenomegaly are less common
- Triad of osteolytic lesion with exophthalmos and diabetes insipidus was used traditionally to described Hand-Schuller-Christian disease

Diagnosis

Diagnosis dependent on clinical, radiologic and pathologic correlation

Radiology description

Osteolytic jaw lesions tend to have a well defined radiolucent appearance
Erosion of the bone around the teeth often gives the appearance that the teeth are floating on the radiolucent lesion
Root resorption of the involved teeth may occur but is not common

Radiology images

Images hosted on other servers:

Lesion on the right side mandible

Multiple ill defined radiolucencies

Lytic lesion

Radiolucent lesion

Root canal treatment

Prognostic factors

LCH is clinically stratified as:
- Single system LCH
  - Patients with single system LCH such as bone LCH generally have a favorable outcome and higher change of spontaneous remission
  - Unifocal bone disease has a good prognosis with relapse rate of ~10% and a disease free survival of 95%
  - Multifocal bone disease has a high relapse rate, ~75%
- Multisystem LCH with two or more organs / systems involved, with or without involvement of "risk organs"
  - Risk organs in LCH include liver, spleen and bone marrow
  - Multisystem LCH are subdivided into "low risk" and "risk" groups
  - High rate of relapse, approximately 95%
  - 75% disease free survival
    - ~17% die of disease (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2005;100:S42)

Case reports

5 year old boy with intermittent pain on the lower right side of the face for one month (J Clin Diagn Res 2016;10:ZD19)
9 year old boy with a firm swelling in right lower jaw along with bilateral submandibular lymphadenopathy for 1 month (J Cytol 2014;31:227)
29 year old male patient presented with a history of painless swelling in the lower jaw for 2 months (BMJ Case Rep 2015 Jan 14;2015)
39 year old man who complained of recurrent pain, swelling of the gingiva and an occasional pus-like discharge in the right mandible for one year (Oncol Lett 2014:8:1075)
39 year old man with pain in the anterior region of the mandible for several months (Imaging Sci Dent 2013;43:117)
Langerhans cell histiocytosis in a periapical cyst (J Tenn Dent Assoc 2008;88:26)
Multiple cases of inflammatory periapical disease with small aggregates of Langerhans cells as a minor component (Oral Surg Oral Med Oral Pathol 1992;74:186)

Treatment

Surgical management is used alone in ~50% of cases
- Additionally, therapy is often dictated by type of involvement (single vs. multisystem LCH)
For single system LCH
- Unifocal bone lesions
  - In most cases, simple curettage or biopsy is diagnostic and will result in healing
  - Indications for treatment include severe pain, restriction of mobility, risk of imminent bone fracture and spinal cord or optic nerve compression (Cancer Treat Rev 2010;36:354)
    - Local therapies include steroid and low dose radiation for optic nerve or spinal cord compression
    - Systemic therapies include indomethacin, bisphosphonates and chemotherapy
      - Important to remember that bisphosphonate use has been associated with osteonecrosis
    - The Histiocyte Society recommends chemotherapy in craniofacial bone lesions with a soft tissue mass extending into the dura (Cancer Treat Rev 2010;36:354)
For Multisystem LCH
- Initial induction or "intensive" chemotherapy is given to all patients with the goal of achieving complete resolution of signs and symptoms
- The combination of vinblastine plus prednisolone is most common induction regimen
Clinical trials for BRAF inhibitors are currently ongoing (ClinicalTrials.gov)

Clinical images

Images hosted on other servers:

Histiocytosis X

Swelling in the right vestibule

Microscopic (histologic) description

Cellular proliferation of sheets of oval mononuclear cells characterized by unique reniform or cleaved nuclei with pale cytoplasm
- Mitotic figures may be abundant
Interspersed inflammation, characteristically eosinophils but plasma cells and lymphocytes can be present
Giant cells are nearly always present and foci of necrosis is common

Microscopic (histologic) images

Images hosted on other servers:

Proliferation of neoplastic Langerhans cells

Various Images

CD1a

Immunohistochemistry & special stains

Positive
- CD1a, S100
- Vimentin, Langerin, variable CD68
Negative
- HAM56, CD21, CD35

Electron microscopy description

Birbeck granules (electron dense cross striations)
For Congenital LCH
- Laminated dense bodies with a concentric myelin-like morphology
  - Also known as vermiform bodies
- Any child less than 2 years with evidence of LCH should have transmission electron microscopy

Electron microscopy images

Contributed by Mark R. Wick, M.D.

Birbeck granules

Electron micrograph

Molecular / cytogenetics description

BRAF V600E mutation identified
- Identified in 57% of LCH
Often loss of DNA sequences involving several chromosomes and 1p (Hum Pathol 2002;33:555)
P53 is overexpressed in LCH but the mechanism is mostly not understood and is not the result of a mutation in TP53

Differential diagnosis

Granulomatosis with polyangiitis (Wegener's):
- Granulomatous and often necrotizing process can target oral tissues (clinically: "strawberry gingivitis")
- Presence of classic triad: vasculitis, tissue necrosis and granulomatous (necrotizing or nonnecrotizing) inflammation is uncommon
  - Other accompanying features may include: fat necrosis, mixed acute and chronic inflammation, geographic fibrinoid degeneration and microabscess formation
- Unusual findings that may lead to consideration of GPA: collagen alterations (mummification of collagen, granular degeneration or frank necrosis) with a rich inflammatory infiltrate that may include many plasma cells, lymphocytes, neutrophils, eosinophils and epithelioid histiocytes
Rosai Dorfman (RD)
- Characterized by enlarged, round histiocytes in contrast to the cleaved, reniform nuclei of LCH
- RD typically has plasma cells instead of eosinophils
- Emperilpoeisis can be highlighted by S100 protein
- RD negative for CD1a
Central xanthoma of the jaw:
- Sheets of of foamy cells with abundant cytoplasm and small hyperchromatic nuclei
- Foreign body type giant cells occasionally present when associated with cholesterol clefts
- Hemorrhage and hemosiderin and chronic inflammatory cells, such as lymphocytes and plasma cells
Radiographically, the differential is broad and includes:
- Lymphoma
- Odontogenic cysts
- Benign and malignant odontogenic tumors
- Reactive / inflammatory processes related to odontogenic infection or inflammation
- Other metastases

Additional references

Oral Surg 2014;7:40, Oral Surg Oral Med Oral Pathol Oral Radiol 2015;119:92, Aust Dent J 2011;56:433

Board review style question #1

A 2 year old child is diagnosed with LCH and transmission electron microscopy shows laminated dense bodies with a concentric myelin-like morphology also known as vermiform bodies. This finding is important because:

LCH with vermiform bodies is resistant to treatment
Vermiform bodies are only present in CD1a negative LCH
Vermiform bodies are only seen in congenital self healing LCH
Vermiform bodies exclude the diagnosis of LCH

Board review style answer #1

C. Vermiform bodies are only seen in congenital self healing LCH

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