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Eosinophilic granuloma, Langerhans cell histiocytosis (LCH), Hennebert's symptom

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Eosinophilic Granuloma (Langerhans Cell Histiocytosis) Overview

Eosinophilic granuloma represents the mildest and most localized form of Langerhans Cell Histiocytosis (LCH). LCH is a rare disorder characterized by the abnormal proliferation and accumulation of Langerhans cells (a type of dendritic cell, part of the immune system) in various tissues [1]. While the exact cause is unknown, recent research suggests LCH is often driven by activating mutations (like BRAF V600E) in the MAPK signaling pathway within the Langerhans cells or their myeloid precursors, leading many to classify it as an inflammatory myeloid neoplasm rather than purely inflammatory or reactive [2]. Historically, LCH encompassed entities known as Hand–Schüller–Christian disease and Letterer-Siwe disease (representing more severe, disseminated forms), and the broader term Histiocytosis X. The terminology was standardized by the Histiocyte Society [3].

Eosinophilic granuloma (EG) typically presents as one (monostotic) or sometimes a few (polyostotic) lytic (destructive) bone lesions. It most commonly affects children and young adults (peak incidence between 5-15 years), though it can occur at any age [4]. Common skeletal sites include the skull (calvarium, temporal bone, mandible - very frequent), ribs, vertebrae (potentially causing vertebra plana - a characteristic flattened vertebral body), pelvis, and long bones (femur, humerus).

Skull CT demonstrating characteristic features of eosinophilic granuloma: well-defined lytic bone lesions, often with sharply demarcated or "beveled" edges due to unequal destruction of the inner and outer tables of the skull. A central bony sequestrum ("button sequestrum") is sometimes seen [5].

When the temporal bone is involved (a frequent site, occurring in 15-60% of LCH cases with bone involvement [6]), eosinophilic granuloma can mimic other conditions, particularly chronic otitis media or mastoiditis. Symptoms may include persistent ear discharge (otorrhea, sometimes bloody), conductive or mixed hearing loss, swelling behind the ear (postauricular mass over the mastoid), ear pain (otalgia), and sometimes the presence of granulation tissue or polyps in the external auditory canal. Facial nerve paresis or paralysis can occur if the lesion erodes the facial canal (Fallopian canal). A fistula tract is uncommon.

Involvement of the petrous apex or inner ear structures can lead to sensorineural hearing loss, dizziness, or vertigo (symptoms of inner ear involvement). Extensive destruction can affect other cranial nerves passing through the temporal bone or skull base (e.g., VI, IX, X, XI, XII).

Radiographically, eosinophilic granuloma appears as a lytic lesion without significant surrounding reactive sclerosis (bone hardening). The lesion edges are typically well-defined ("punched-out") but non-sclerotic. On MRI, the lesion usually shows intermediate signal on T1-weighted images, high signal on T2-weighted images (reflecting inflammatory cells and edema), and avid, often homogeneous enhancement after gadolinium administration [7]. Associated soft tissue mass is common.

Solitary eosinophilic granuloma (single bone lesion) generally carries an excellent prognosis and may even regress spontaneously through fibrosis over time [4]. However, multifocal bone disease (polyostotic eosinophilic granuloma) or multisystem LCH (involving skin, pituitary, liver, spleen, lungs, bone marrow) indicate more extensive disease with a less favorable prognosis and a higher risk of recurrence or progression, potentially requiring systemic therapy. While typically behaving benignly, the neoplastic nature driven by MAPK pathway mutations is now recognized [1].

A T1-weighted, post-contrast coronal MRI reveals a homogenously enhancing soft tissue mass in the superotemporal aspect of the left orbit, originating from and destroying the adjacent bone, consistent with eosinophilic granuloma involving the orbital bones.

Eosinophilic Granuloma Diagnosis

The definitive diagnosis of eosinophilic granuloma requires a tissue biopsy. Surgical sampling, often performed via curettage or open biopsy of the affected bone (e.g., mastoid process if involved, skull lesion), provides tissue for histological and immunohistochemical analysis [4].

Histopathology classically reveals a mixed inflammatory infiltrate dominated by the characteristic Langerhans cells, which are large cells with abundant eosinophilic cytoplasm and distinctive grooved, folded, or indented ("coffee bean") nuclei. These pathognomonic cells typically stain positive for immunohistochemical markers **CD1a** and **Langerin (CD207)** (more specific than S100) [8, 9]. S100 protein is also usually positive but less specific. Varying numbers of eosinophils (often numerous, giving the lesion its historical name), lymphocytes, plasma cells, neutrophils, and multinucleated giant cells (osteoclast-like) are also present within a background of non-Langerhans histiocytes. Areas of necrosis may sometimes be seen.

Histopathological examination of biopsied tissue (H&E stain) shows an infiltrate containing Langerhans cells (larger cells with irregular or indented nuclei), numerous eosinophils (cells with bilobed nuclei and bright red cytoplasmic granules), neutrophils, histiocytes, and lymphocytes, supporting the diagnosis of eosinophilic granuloma (LCH). Confirmation requires positive CD1a and Langerin immunostaining.

Imaging plays a crucial role in identifying suspicious lesions, determining their extent, assessing involvement of adjacent structures (e.g., dura, orbit, facial nerve canal), guiding biopsy, and screening for additional lesions (staging). Essential imaging includes:

  • Plain Radiography (X-rays): Can show characteristic lytic ("punched-out") lesions, often in the skull or long bones, typically without a sclerotic rim. Vertebral involvement may show flattening (vertebra plana).
  • CT Scan: Provides excellent detail of bone destruction, including the typical "beveled edge" appearance in skull lesions due to differential erosion of inner and outer tables. Useful for assessing temporal bone involvement (ossicular chain, facial nerve canal, labyrinthine erosion) and planning biopsy/surgery.
  • MRI: Best for evaluating the soft tissue component of the lesion, associated inflammation/edema in adjacent tissues (marrow, muscle, dura), involvement of adjacent structures (like the dura, orbit, pituitary stalk), and differentiating from purely cystic lesions. Shows avid contrast enhancement of the solid components.
  • Skeletal Survey or Whole Body Low-Dose CT: Used historically/currently to screen for multiple bone lesions in patients diagnosed with LCH, important for staging (single vs. multiple bone sites).
  • 18F-FDG PET-CT: Increasingly used for staging, assessing disease activity, identifying occult lesions (especially non-osseous), and monitoring treatment response in multisystem or polyostotic LCH [10].

Differential Diagnosis of Lytic Bone Lesions (esp. Skull/Temporal Bone)

Condition Key Features / Distinguishing Points Typical Imaging / Lab Findings
Eosinophilic Granuloma (LCH) Children/young adults typically. Well-defined lytic lesion(s), often skull/femur/ribs/vertebrae. Beveled edge in skull. Temporal bone involvement common (mimics otitis). Minimal sclerosis. X-ray/CT: Lytic lesion, non-sclerotic margin, beveled edge, +/- button sequestrum. MRI: T1 intermediate, T2 bright, enhances avidly, associated soft tissue mass. Biopsy: Langerhans cells (CD1a+, CD207+), eosinophils.
Osteomyelitis (often secondary to Sinusitis or Otitis) Bone infection. Pain, swelling, fever, drainage possible. Often history of trauma, surgery, or adjacent infection. Ill-defined margins common. X-ray: Lytic destruction, periosteal reaction, sequestrum (later stages), ill-defined margins. CT: Bone destruction, soft tissue swelling/abscess. MRI: Marrow edema (T2 bright, T1 dark), cortical disruption, enhancement, adjacent soft tissue inflammation/abscess. Elevated ESR/CRP. Biopsy/culture positive.
Metastatic Disease (e.g., Neuroblastoma in children; Lung, Breast, Prostate, Kidney in adults) Age group depends on primary. Known primary cancer often. Often multiple lesions. Pain common. X-ray/CT: Lytic (e.g., lung, kidney) or blastic (e.g., prostate, breast) or mixed lesions, variable margins. MRI: Variable signal, enhancement, marrow replacement. Bone scan usually positive (except myeloma). Biopsy confirms metastasis. Search for primary tumor.
Multiple Myeloma Plasma cell malignancy. Older adults typically (>50). Bone pain, pathological fractures, anemia, renal failure, hypercalcemia. Multiple "punched-out" lytic lesions common, sharply defined, no sclerosis. X-ray: Multiple well-defined punched-out lytic lesions (esp. skull, spine, pelvis). MRI sensitive for diffuse marrow involvement. Serum/urine protein electrophoresis (M-spike), serum free light chains, bone marrow biopsy diagnostic. Bone scan often falsely negative.
Primary Bone Tumor (e.g., Ewing Sarcoma, Lymphoma, Osteosarcoma, Chordoma) Variable age depending on type. Ewing/Osteosarcoma common in children/adolescents. Lymphoma variable. Chordoma skull base/sacrum. Pain, swelling. Appearance varies greatly. X-ray/CT/MRI: Appearance depends on tumor type (e.g., Ewing: permeative lysis, onion skin periostitis; Osteosarcoma: lytic/blastic, sunburst periostitis; Lymphoma: often permeative). Biopsy essential for diagnosis.
Epidermoid / Dermoid Cyst Congenital inclusion cysts. Slow growing, often skull (esp. diploic space). Smoothly marginated lytic lesion often with well-defined sclerotic rim. Usually asymptomatic unless large or complicated. CT: Lytic lesion, sharp sclerotic rim. MRI: Epidermoid - CSF-like signal (T1 low, T2 high), restricts diffusion (DWI bright). Dermoid - Fat signal (T1 bright, fat suppressed on specific sequences), may contain hair/teeth (calcification). Minimal/no enhancement usually.
Cholesteatoma (Temporal Bone) (related to Otogenic Complications) Keratin debris collection in middle ear/mastoid. History of chronic ear disease/retraction pockets. Progressive conductive hearing loss, otorrhea. Causes pressure erosion of bone. CT: Soft tissue mass in middle ear/mastoid with characteristic bone erosion (esp. ossicles, scutum, lateral semicircular canal). MRI: T1 hypo, T2 hyper, variable DWI (often restricts), minimal/no central contrast enhancement (may show peripheral rim).
Fibrous Dysplasia Benign fibro-osseous developmental lesion, replaces normal bone. Bone expansion, "ground-glass" matrix appearance common. Often skull/facial bones, ribs, femur. Usually presents adolescence/young adult. CT: Expansile lesion, ground-glass matrix typical, well-defined but often irregular margins blending with normal bone. MRI: Variable signal (depends on fibrous/cystic/osseous components), variable enhancement.
Giant Cell Granuloma / Giant Cell Tumor of Bone GCG common in mandible/maxilla, GCT typically epiphyseal in long bones but can occur in skull base. Lytic, sometimes expansile lesions. Imaging shows lytic lesion, often well-defined, may be expansile. GCT often has low T2 signal due to hemosiderin. Biopsy needed (multinucleated giant cells in stromal background).

 

Once LCH is diagnosed via biopsy, staging investigations are performed to determine the extent of disease (single bone lesion, multiple bone lesions, involvement of skin, lymph nodes, pituitary, liver, spleen, lungs, bone marrow) and identify any "risk organ" involvement (liver, spleen, hematopoietic system), as defined by the Histiocyte Society criteria. This staging is crucial for prognosis and determining the appropriate treatment strategy [4, 1].

 

Eosinophilic Granuloma Treatment

Treatment strategy for LCH depends critically on the extent of disease (single system vs. multisystem) and the involvement of specific organs/sites.

  • Localized Eosinophilic Granuloma (Single System, Single Bone Lesion - SS-s):
    • Observation: For asymptomatic lesions discovered incidentally in non-critical locations (e.g., rib, calvarium without neurological signs), observation with serial imaging (e.g., every 3-6 months initially) may be a reasonable option, as spontaneous regression can occur, particularly in young children [11].
    • Intralesional Corticosteroid Injection: Injection of methylprednisolone directly into the lesion can induce healing and is often considered a first-line treatment for accessible lesions, especially in weight-bearing bones or vertebrae where stability is a concern, or to avoid morbidity of surgery [12].
    • Curettage +/- Bone Grafting: Surgical removal of the lesion contents (curettage) is frequently performed both for obtaining diagnostic tissue (biopsy) and for treatment, particularly for symptomatic lesions or those causing structural instability. Bone grafting may be needed to fill larger defects or ensure stability, especially in weight-bearing bones or spine [13]. During surgery for temporal bone lesions, the characteristic yellowish-brown, soft, friable, granular tissue is encountered; critical structures like the dura, sigmoid sinus, or facial nerve may be exposed by the lesion and must be carefully identified and preserved.
    • Low-Dose Radiotherapy (RT): Highly effective for controlling local disease, RT is typically reserved for lesions in locations where surgery or injection is difficult or risky, or carries high morbidity (e.g., spine with neurological compromise, critical skull base locations, orbital lesions threatening vision), or for refractory/recurrent solitary lesions. Doses are generally low (e.g., 6-12 Gy) to minimize long-term risks, especially in children [14].
  • Single System, Multifocal Bone Disease (SS-m) or Multisystem LCH (MS): Requires systemic therapy, usually managed by pediatric or adult oncologists/hematologists specializing in histiocytic disorders, often according to clinical trial protocols or established guidelines (e.g., from the Histiocyte Society).
    • Standard first-line therapy often involves chemotherapy with **vinblastine and prednisone** for 6-12 months [15, 16].
    • More intensive therapies or alternative agents (e.g., cytarabine, cladribine, clofarabine, methotrexate) may be used for patients with risk organ involvement (liver, spleen, hematopoietic system) or refractory/relapsed disease.
    • Targeted therapies (e.g., BRAF inhibitors like vemurafenib or dabrafenib) are emerging as options for patients with specific mutations (like BRAF V600E), particularly in refractory cases [17].
    • Surgery or radiotherapy may still play an adjunctive role for specific problematic lesions (e.g., spinal instability, impending fracture, pain relief) within the context of systemic treatment.

For temporal bone eosinophilic granuloma treated surgically, the extent of surgery depends on the lesion's location and involvement of critical structures. Complete removal is often attempted if feasible without causing significant neurological deficit. Postoperative radiotherapy is now used much less frequently for localized disease due to long-term risks. Systemic corticosteroids alone are generally not considered sufficient primary therapy for bone lesions but are part of systemic chemotherapy regimens.

 

Hennebert's Symptom (Sign)

Hennebert's sign or symptom refers to the induction of transient nystagmus and/or vertigo (a subjective sensation of spinning or movement) by applying positive or negative pressure to the external auditory canal (EAC), typically using a pneumatic otoscope or by performing the fistula test (alternating pressure on the tragus) [18]. It indicates an abnormal mechanical linkage or sensitivity between the air pressure changes in the EAC/middle ear and the inner ear vestibular system (labyrinth).

A positive Hennebert's sign (eliciting reproducible vertigo/nystagmus with pressure changes) suggests several possible underlying pathologies [19]:

  • Labyrinthine Fistula: An abnormal opening between the perilymphatic space of the inner ear and the middle ear cavity. Most commonly caused by cholesteatoma eroding the bony labyrinth (usually the horizontal semicircular canal), but can also result from chronic otitis media, temporal bone trauma, or previous ear surgery (e.g., stapedectomy). Pressure changes are directly transmitted to the inner ear fluids.
  • Tertiary Syphilis (Otosyphilis): Hennebert first described the sign in patients with congenital syphilis affecting the inner ear. Inflammation and potentially fibrous adhesions involving the labyrinthine windows or membranes might mediate the pressure sensitivity.
  • Meniere's Disease: Hennebert's sign is occasionally positive in Meniere's disease (estimated 3-30% of cases). The proposed mechanism involves endolymphatic hydrops (distension of the inner ear fluid spaces), where a distended saccule may adhere to the inner surface of the stapes footplate. Pressure applied to the tympanic membrane and transmitted via the ossicles then directly stimulates the abnormally positioned saccule.
  • Perilymphatic Fistula: A leak of inner ear fluid (perilymph) into the middle ear, often at the oval or round window, typically following head trauma, barotrauma, or stapes surgery. Pressure changes can induce fluid shifts within the inner ear, causing vestibular symptoms (though Tullio phenomenon - sound-induced vertigo - is more characteristic).

The sign itself is elicited by applying gentle, brief positive and negative pressure changes within the sealed EAC using a pneumatic otoscope while observing the patient's eyes for nystagmus (often torsional or horizontal) and inquiring about subjective vertigo. The direction of nystagmus may vary with positive vs. negative pressure. It's important to distinguish this from simple movement induced by pushing on the head.

References

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  2. Badalian-Very G, et al. Recurrent BRAF mutations in Langerhans cell histiocytosis. Blood. 2010 Sep 16;116(11):1919-23. doi: 10.1182/blood-2010-04-279083
  3. Writing Group of the Histiocyte Society. Histiocytosis syndromes in children. Lancet. 1987 Jan 24;1(8526):208-9. doi: 10.1016/s0140-6736(87)91191-1
  4. Haupt R, Minkov M, Astigarraga I, et al. Langerhans cell histiocytosis (LCH): guidelines for diagnosis, clinical work-up, and treatment for patients till the age of 18 years. Pediatr Blood Cancer. 2013 Feb;60(2):175-84. doi: 10.1002/pbc.24367
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  9. Chapter on Histiocytic Disorders. In: Knowles DM, ed. Neoplastic Hematopathology. 3rd ed. Lippincott Williams & Wilkins; 2010.
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  11. Lee JS, et al. Spontaneous Regression of Solitary Eosinophilic Granuloma of the Skull. J Korean Neurosurg Soc. 2008;44(5):328-31. doi: 10.3340/jkns.2008.44.5.328
  12. Egeler RM, et al. Intralesional corticosteroid injection for Langerhans cell histiocytosis of bone. J Pediatr Orthop. 1998;18(3):332-9.
  13. Yasko AW, et al. Curettage and bone grafting for eosinophilic granuloma of bone. Clin Orthop Relat Res. 1998;(351):227-36. doi: 10.1097/00003086-199806000-00029
  14. Kriz J, et al. Radiotherapy in Langerhans Cell Histiocytosis - A Rare Indication in the Era of Systemic Therapy? Strahlenther Onkol. 2018;194(1):1-9. doi: 10.1007/s00066-017-1208-7
  15. Gadner H, et al; Histiocyte Society. A randomized trial of treatment for multisystem Langerhans' cell histiocytosis. J Pediatr. 2001;138(5):728-34. doi: 10.1067/mpd.2001.114128
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