Other Tumors of Undefined Neoplastic Nature

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Ovid: Oncology and Basic Science

Editors: Tornetta, Paul; Einhorn, Thomas A.; Damron, Timothy A.

Title: Oncology and Basic Science, 7th Edition

> Table of Contents > Section
II – Specific Bone Neoplasms and Simulators > 5 – Benign Bone Tumors
> 5.8 – Other Tumors of Undefined Neoplastic Nature

5.8

Other Tumors of Undefined Neoplastic Nature

Sean V. McGarry

C. Parker Gibbs

Langerhans cell histiocytosis (LCH) and Erdheim-Chester
disease (ECD) are histiocytoses: rare benign lesions of bone in which
the proliferating tumor cell of origin is a histiocyte. There are two
types of histiocytes: (1) macrophages arising from monocytes and (2)
dendritic cells arising from Langerhans cells. In LCH the involved cell
is a Langerhans cell, in ECD a macrophage. Histiocytoses in general
exist in multiple forms, ranging from a solitary lesion to a diffuse
systemic disease, and they can affect any organ or tissue in the body.
This section deals with the two histiocytoses involving bone: LCH and
ECD. LCH is most commonly a solitary lesion occurring in children and
young adults and often requires surgical intervention. ECD is often a
systemic disease of older adults and very rarely involves surgical
intervention.

Erdheim-Chester Disease

The original description of ECD was made by Chester in
1930. In 1972, Jaffe first used the eponym ECD to recognize that
description. In 1983, a review of the literature by Alper found that 47
cases had been described up to that point. ECD remains an extremely
rare entity; thus, our knowledge of the natural history of the disease
and its treatment is somewhat limited. Its etiology is unknown.

Pathogenesis

Epidemiology

Typically a disease of older adults (Fig. 5.8-1)
- Age range 7 to 84 years
- Mean age 53 years
Slight male predominance
Affects long bones most commonly
- Bilateral and symmetric
- Classically affects diaphysis and metaphysis, sparing epiphysis (not always)
- Lower extremity (femur, tibia, fibula) more common than upper extremity (humerus, radius, ulna)
Usually spares flat bones

Pathophysiology

Systemic lipid storage disorder affecting histiocytes
Lipid-laden histiocytes form granulomas in bones, other organs or tissues.

Prognosis and Natural History

Because of the infrequency of the disease, little is known about prognostic factors.

Figure 5.8-1
Sex and age at time of diagnosis for 59 patients with Erdheim-Chester
disease. (After Veyssier-Belot C, Cacoub P, Caparros-Lefebvre D, et al.
Erdheim-Chester disease: Clinical and radiologic characteristics of 59
cases. Medicine 1996;75:157–169.)

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Prognosis is related to extent of visceral involvement.
- In some patients the disease is quiescent.
- In most patients the disease is progressive, and patients die of end-organ failure
  - Respiratory distress or pulmonary fibrosis
  - Heart failure
  - Renal failure

Classification

There currently is no accepted classification scheme for ECD.

Diagnosis

Physical Examination and History

A definitive diagnosis requires the combination of history, physical examination findings, radiographs, and a tissue diagnosis.
Classical radiographic findings with
bilateral, symmetric osteosclerosis of the diaphysis and metaphysis
with epiphyseal sparing can be considered pathognomonic.

Clinical Features

Depends on the organ systems affected (Table 5.8-1 and Fig. 5.8-2)

Radiologic Features

Densely sclerotic changes of the metaphysis and diaphysis, with coarsened trabeculae
- Typically spares the epiphysis
- Rarely, lesions are more lytic in nature.
Long bones most commonly affected (Fig. 5.8-3)
- Lower extremities more commonly affected than upper extremities

Table 5.8-1 Clinical Manifestations of Erdheim-Chester Disease According to Organ of Involvement

Site of Involvement	Clinical Manifestation
Bone	Bone pain
Kidney	Hypertension Renal failure
Retrobulbar region	Exophthalmos
Pericardium	Pericarditis
Pituitary gland	Diabetes insipidus
Lungs	Pulmonary fibrosis
Skin	Xanthomas
Central nervous system	Confusion Ataxia
Adapted from Veyssier-Belot C, Cacoub P, Caparros-Lefebvre D, et al. Erdheim-Chester disease: Clinical and radiologic characteristics of 59 cases. Medicine 1996;75:157–169.

Figure 5.8-2
Prevalence of clinical signs in 59 patients with Erdheim-Chester
disease. (After Veyssier-Belot C, Cacoub P, Caparros-Lefebvre D, et al.
Erdheim-Chester disease: Clinical and radiologic characteristics of 59
cases. Medicine 1996;75:157–169.)

Diagnostic Workup Algorithm

Radiographs are nearly always pathognomonic for ECD.
When seen in concert with typical
complaints of bone pain, exophthalmos, diabetes insipidus, or
xanthomas, these patients are not a diagnostic challenge.
They can show elevated erythrocyte sedimentation rate, alkaline phosphatase, or serum lipid profiles.
- However, laboratory testing is unreliable and nonspecific.
Figure 5.8-3 Radiograph of patient with Erdheim-Chester disease showing typical radiographic changes.

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If there is any question as to the diagnosis, a biopsy of an accessible skeletal lesion is performed.
- Histopathologic evaluation demonstrates
  infiltration of the bone by foamy, lipid-laden histiocytes, with giant
  cells and rare lymphocytes.
- Immunostaining demonstrates negative staining for both S-100 and CD1a (which would suggest the diagnosis of LCH).

Treatment

Surgical and Nonoperative Options

Occasional need for biopsy to confirm diagnosis
No need for surgical intervention other than rare prophylactic fixation to prevent fracture
No good nonoperative treatment options, but historically patients are treated with any combination of the following:
- Steroids
- Chemotherapy
- Radiation

Results and Outcome

Overall Outcome

With no good treatment options for ECD, overall survival
is rather bleak. In a review of 37 patients followed for an average of
30 months, Veyssier-Belot reported a mortality rate of 59%. Other
reports suggest a mortality rate of approximately 33%, but with limited
follow-up. Patients die of end-organ failure (pulmonary fibrosis, heart
failure, or renal failure most commonly).

Specific Treatment Outcome

Because there is not a consensus as to the appropriate
treatment of ECD in combination with the rarity of the diagnosis, there
are not sufficient numbers to assess specific treatment outcomes. In
the review by Veyssier-Belot, the following results are presented:

Steroid therapy alone in 12 patients
- Effective transiently in 4 patients
- Ineffective in 8
Chemotherapy in combination with steroids in 8 patients
- 4 patients improved
- No effect in 4 patients
Radiation therapy in 6 patients
- Transiently effective in 3 for bone pain
- Not effective in 3 to treat exophthalmos

Langerhans Cell Histiocytosis

In 1953, Lichtenstein, noting the histological
similarities in eosinophilic granuloma, Hand-Christian-Schüller, and
Letterer-Siwe, coined the term “histiocytosis X” as a general term to
encompass all three diagnoses. We know today that all three diseases
originate from a Langerhans cell and refer to the group of disorders as
the Langerhans cell histiocytoses (LCH) or granulomatoses. The three
share a common histopathology and are considered to be clinical
variations of the same disease.

Pathogenesis

Etiology

Unknown
- Possibly autoimmune
- Possibly viral infection

Epidemiology

Eosinophilic Granuloma

Solitary or multiple lesions of bone, but most commonly solitary (80%)
Age and gender
- Can occur at any age
- Most patients are between 5 and 20.
- Male:female ratio 2:1
Location
- Flat bones > long bones
- Skull, pelvis, ribs, spine (anterior column)
- In long bones, occurs in diaphysis and metaphysis
- Rare in hands, feet, posterior column of spine, epiphysis of long bones

Hand-Christian-Schüller

Disseminated, more severe
Three names (Hand-Christian-Schüller): think clinical triad:
- Bone lesions (usually skull)
- Exophthalmos
- Diabetes insipidus
Age and gender
- Most <5 years
- Male:female closer to 1:1 than solitary eosinophilic granuloma
Location
- Multifocal
- Very common in skull and jawbones
- Can occur in hands, feet

Letterer-Siwe

Disseminated, nearly always fatal
- Extensive cutaneous lesions
- Hepatosplenomegaly
- Fevers/infections
Age/gender
- Nearly all <2 years (two names [Letterer-Siwe]: think 2 years)
Location
- Ends up involving nearly the entire skeleton

Pathophysiology

The reticuloendothelial system is a key component of the immune system involved in phagocytizing foreign material and debris.

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Langerhans cells are an important part of that system.
- They originate in the bone marrow and then move to the lymph nodes, liver, lung, spleen, and skin.
- LCH is a proliferation of these cells.
Figure 5.8-4
Typical histopathology section from bony LCH lesion shows the key
langerhans histiocytes (large, basophilic, cleared, coffee-bean shaped
nuclei) and eosinophils.
This is followed by a granulomatous reaction by the body, with the characteristic eosinophilic cell population.
It is the Langerhans cell that is
required for the histological diagnosis, not the ubiquitous eosinophil,
making the name “eosinophilic granuloma” a bit of a misnomer.

Table 5.8-2 Staging System for Langerhans’ Cell Histiocytosis

Stage	Description
I
Ia	Single monostotic bone lesion
Ib	Multiple bone lesions
II	Age >2 years at diagnosis, having one or more of the following systems involved: Diabetes insipidus Teeth and gingivae Lymph nodes Skin Seborrhea Mild lung involvement Bone marrow focally positive
III
IIIa	Age <2 years at diagnosis, having any of the above systems involved
IIIb	Age >2 years at diagnosis, with involvement of following: Liver and/shor spleen Massive nodal involvement Major lung involvement Bone marrow packed
IV	Spleen >6 cm palpable below costal margin and fever >1 month with or without any or all of the above systems involved
V	Monocbtosis in peripheral blood >20% of differential cell count, in addition to stage III or IV findings
Adapted from Greenberger JS, Crocker AC, Vawter G, et al. Results of treatment of 127 patients with systemic histiocytosis. Medicine (Baltimore) 1981;60:311–338.

Classification

Solitary lesions of eosinophilic granuloma are staged as benign bone tumors.
- Latent
- Active
- Aggressive
LCH defies most conventional bone tumor classification schemes (Table 5.8-2).

Diagnosis

Physical Examination and History

Physical examination and history can vary greatly with LCH, based on the subtype.
Often in Hand-Christian-Schüller or
Letterer-Siwe, the patient has already been given a diagnosis by the
pediatrician before he or she is referred to the orthopaedic surgeon.
A history of localized or referred pain often results from a solitary bone lesion.
Patients may also be asymptomatic, the lesions being discovered incidentally on radiographs done for other reasons.

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Clinical Features

Eosinophilic Granuloma

Typically patients present with localized bone pain.
Occasionally referred pain from a proximal site
- Example: knee pain with normal x-ray, get hip x-ray
Younger patients may present with limp or refusal to bear weight.

Hand-Christian-Schü

Classic triad is not all that classic (only 10% to 20%).
- Bone lesions (typically skull)
- Exophthalmos
- Diabetes insipidus

Letterer-Siwe

Bone lesions are not the typical initial presentation.
Fevers/infections
Exophthalmos
Hepatosplenomegaly
Lymphadenopathy
Cutaneous lesions
- Papular rash

Radiologic Features

Eosinophilic Granuloma

Destructive, poorly marginated, lucent lesions (Fig. 5.8-5)
- One of the “great mimickers,” along with osteomyelitis (Fig. 5.8-6)
- Usually based in the medullary canal
- Later or healing lesions may have a cortical rim (Fig. 5.8-7).
  
  Figure 5.8-5 A destructive poorly marginated lesion in the scapula of a 5-year-old girl.
  
  Figure 5.8-6 Note the radiolucent nature of eosinophilic granuloma in this femoral lesion found in a 12-year-old boy.
- When they occur in flat bones, they may resemble Ewing sarcoma.
Vertebral body involvement
- Vertebra plana (Fig. 5.8-8)
Occasionally larger lesions show cortical
destruction and periosteal reaction (resembling osteosarcoma, Ewing
sarcoma, or osteomyelitis) (Fig. 5.8-9).

Hand-Christian-Schüller

Radiographically similar to eosinophilic granuloma lesions
- Multiple
- Larger
- May have a bubbly appearance as lesions overlay

Letterer-Siwe

More subtle than eosinophilic granuloma or Hand-Christian-Schüller
Lesions are smaller.

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Figure 5.8-7 Axial CT of a well-corticated lesion in the posterior wall/column of an 18-year-old man.

Diagnostic Workup

Work-up of a patient with lucent lesion suspicious for eosinophilic granuloma
- Orthogonal radiographs
- Possibly axial imaging (computed tomography [CT]/magnetic resonance imaging [MRI])
- Bone scan or skeletal survey to rule out
  polyostotic disease, based on other symptoms or clinical suspicion for
  polyostotic disease. However, approximately 30% of the lesions do not
  show increased uptake on bone scan, making bone scan less reliable than
  skeletal survey.
- Biopsy

Figure 5.8-8 Radiographic findings of vertebra plana. Arrow indicates a flattened L4 vertebrae, secondary to eosinophilic granuloma.

Treatment

Surgical Indications/Contraindications

Usually biopsy is required to rule out other more serious diagnoses on the differential
- Ewing sarcoma
- Osteomyelitis
- Osteosarcoma
- Leukemia/lymphoma
Once a diagnosis is made, surgical indications depend on symptoms, location, size, and number of lesions.
- Painful solitary lesions may warrant a curettage and bone graft, particularly if able to be done coincident with an open biopsy.
- Impending pathologic fractures should be considered for curettage and prophylactic stabilization.
  
  Figure 5.8-9 Axial cut of a T2-weighted MRI image showing extensive edema in the soft tissue of this distal humeral lesion.
- Numerous small lesions
  (Hand-Christian-Schüller or Letterer-Siwe) typically don’t require
  surgery but will require chemotherapy and/or radiation therapy.
- Some authors have suggested the use of corticosteroid injection, but with mixed results.

Surgical and Nonoperative Options

Surgical
- Biopsy
- Curettage/bone graft
- Prophylactic stabilization
- Aspiration and steroid injection
Chemotherapy (for multiple or resistant lesions)
- Vinblastine
- Etoposide
- Prednisone
- Methotrexate
- 6-mercaptopurine
Radiation therapy
- Consider for vertebral lesions at risk of collapse.
  - Establish diagnosis first (usually CT-guided needle biopsy) to avoid mistreatment of Ewing sarcoma or lymphoma.
  - Low dose (500 to 800 cGy)
- Other inaccessible symptomatic lesions

Preoperative Planning

Plan biopsy tract.
Consider surgical adjuvant (phenol,
liquid nitrogen, or argon-beam coagulation). This theoretically offers
a lower recurrence rate, although most reports in the literature are
small series or case reports.

Surgical Goals, Techniques, and Approaches

Depend on location, size, symptoms
Intralesional curettage with or without surgical adjuvant vs. aspiration and steroid injection

Complications

Degenerative changes can occur in periarticular lesions that have been curettaged; consider an adjuvant.
Neurologic symptoms in vertebral lesions
Pathologic fracture

Results and Outcome

Results and outcome vary significantly based on extent of systemic involvement.

Solitary Eosinophilic Granuloma

Solitary eosinophilic granuloma will occasionally heal on its own.
When it does not, simple curettage and bone graft is usually curative, with a low recurrence rate.
Almost all solitary lesions ultimately heal.
Usually the reason to treat it surgically is to establish the diagnosis and rule out a malignant diagnosis.

Systemic Disease

Results and outcome for systemic disease not as good
Because of the rarity of the disease and
the lack of standardized protocols, there are not many reports in the
literature on outcome other than case reports.
Age of diagnosis is a significant prognostic indicator.
- Diagnosis at 2 years of age or younger (typically Letterer-Siwe): 10-year survival 42%
- Diagnosis in patients >2 years of age (usually Hand-Christian-Schüller): 85% 10-year survival
Patients who survived had higher
incidence of developmental delays, mental retardation, and secondary
malignancies, though these data were from patients treated from 1941 to
1975, and chemotherapy and radiation therapy have improved considerably
since that time.

Postoperative Management

Anatomic location dictates the need for protected weight bearing.
Patients with solitary lesions of eosinophilic granuloma should be followed closely until the lesion heals.
- After the lesion heals, these patients are followed by routine surveillance to rule out recurrence.
Patients treated with low-dose radiation
are at an extremely low risk of radiation-induced sarcoma, but this
should be kept in mind.
Patients with Hand-Christian-Schüller or
Letterer-Siwe will require pediatric oncology to manage their
chemotherapy and course of their disease.