20 - 117: HISTIOCYTOSIS Flashcards
Most sensitive marker since this is associated with Birbeck granules
CD 207
Most common presentation of this disease is neck lymphadenopathy observed after an infectious disease.
Biopsy was done revealing lymphocytes or neutrophils found in the cytoplasm of histiocytes with a background of mature lymphocytes and plasma cells
Sinus histiocytosis with massive lymphadenopathy
This is ** Rosai Dorfman Disease**
Mature lesions of juvenile xanthogranuloma are characterized by the presence of foam cells, touton giant cells and foreign body giant cells. Histopath stains for Stabilin -1, S100 and CD1a would show:
(+) Stabilin – 1, (-) S100, (-) CD1a
Characterized by ultrastructural presence of worm-like bodies or histiocytosis with intracytoplasmic worm-like bodies
Benign cephalic histiocytosis
Most common non-cutaneous organ involved in LCH
Bone
Most common endocrinopathy encountered in LCH
Diabetes insipidus
This variant of NLCH preferentially affects male children presenting as sudden appearance of discrete, generalized, small yellow-red to brown papules and nodules with a predilection of flexural and intertriginous areas, as well as mucous membranes
a. Generalized eruptive histiocytoma
b. Xanthoma disseminatum
c. Multicentric histiocytosis
d. Necrobiotic xanthogranuloma
Answer: B. p. 2035
- A. – affects adults
- C. – appears around the age of 50 years, twice as common in females, yellow-brown papules over wrist and fingers
- D. yellowish plaques that ulcerate
This variant of NLCH is characterized by persistent fever, splenomegaly with cytopenia, hypertriglyceridemia, and hypofibrogenemia
a. Rosai-Dorfman Disease
b. Hemophagocytic lymphohistiocytosis
c. Juvenile Xanthogranuloma
d. Benign cephalic histiocytosis
Answer: B. p. 2032 overall mortality is 50%. Treatment options: high-dose corticosteroids, cyclosporine, etoposide, MTX, vincristine
Long bone involvement is almost universal in this type of NLCH
a. Rosai-Dorfman Disease
b. Hemophagocytic lymphohistiocytosis
c. Multicentric histiocytosis
d. Erdheim Chester disease
Answer: D. p. 2038
Langerhans cells are positive with what immunohistochemical stains
CD1a/ S100B/CD207
most aggressive acute LCH multisystem variant with apparent systemic symptoms such as fever, hepatosplenomegaly, polylymphadenopathy, anemia, arthralgia, malaise, and weight loss
Letterer-Siwe disease
organs commonly affected in Letterer-Siwe disease
lung, the bone marrow, and the brain
this is a poor prognostic sign in Letterer-Siwe disease
purpura
60% of LCH biopsy specimens bear this mutation
BRAF-V600E somatic point mutation
these variants of LCH have no systemic involvement
- Hashimoto-Pritzker Disease
- Eosinophilic Granuloma (Unifocal LCH)
benign clinical variant typically presenting with multiple firm red-brown nodules with an elevated border or papulovesicular and papulocrusted lesions mostly on the scalp and face in the **first few months and years of life. **
These lesions usually heal within 2 to 3 months and occasionally leave whitish atrophic scars.
Hashimoto-Pritzker disease
mainly benign isolated or multifocal osteolytic bone LCH, which sometimes affects the skin and mucous membranes
Eosinophilic granuloma
these variant of LCH may present with nodulo-ulcerative lesions in the mouth
- Eosinophilic Granuloma
- Hand-Schüller-Christian disease
Triad of Hand-Schüller-Christian disease
- Diabetes Insipidus
- Bone Lesions
- Exophthalmos
this variant of LCH is lethal if untreated
Letterer-Siwe disease
affected areas in Single-system LCH from most to least common
- Bone
- Skin
- Lymph nodes
- Lungs
- CNS
what are the high risk organs in LCH?
- Hematopoietic system
- Liver
- Spleen
second most common organ involved after bone lesions and can be the earliest sign of disease in LCH
cutaneous findings
skin manifestations of LCH
- most typical ones are s**mall, translucent rose-yellowish crusted papules or papulovesicles **on the trunk, in the intertriginous areas and the scalp, associated with eczematous scaling which resembles “candida intertrigo” or “seborrheic dermatitis”
- Lesions can also present as hemorrhagic papules and nodules associated with petechiae reminiscent of vascular lesions or “varicella-like eruptions”
- Vesicles, pustules, and nail involvement have been described
These findings seem to be associated with a higher risk for multisystem LCH
Mucosal lesions and external otitis media
most common noncutaneous organ involved in LCH
BONE
- bone (77% of cases),
- lymph nodes (19%),
- liver (16%),
- spleen (13%),
- lung (10%),
- CNS (6%).
In children with LCH, what is the most commonly involved bone ?
cervical vertebrae
*which can lead to vertebra plana
most frequently affects the skull, jaw, femur, rib, vertebra, and humerus
In adults with LCH, what is the most common manifestation of bone involvement?
Asymmetric Vertebral collapse
can be one of the most prominent diagnostic hints for LCH - vertebral collapse
most commonly involved lymph node in LCH
Cervical LN
These are among the most serious complications of LCH.
Cholestasis and sclerosing cholangitis induced by hepatic involvement of LCH
The most common manifestations of CNS involvement in LCH
diabetes insipidus, and neurodegenerative symptoms
Endocrine abnormalities resulting from large pituitary tumors, most frequently diabetes insipidus, and neurodegenerative symptoms such as ataxia, dysarthria, cognitive dysfunction, and behavior changes.
most common endocrinopathy encountered in LCH
Diabetes insipidus
Patients present with polyuria, polydipsia, and nocturia.
Histology of Langerhans cell histiocytosis (LCH)
Histopathologically, typical findings in a skin biopsy show a dense and band-like infiltration of the papillary dermis with LCH cells (Fig. 117-7). These cells are oval shaped with an eosinophilic cytoplasm and typically display an irregular, vesicular, and infolded (kidney-shaped) nucleus
Langerhans cell histiocytosis is postitive to what immunohistochemical stains?
Positive: CD1a, CD2, CD11b, CD11c, CD13, CD66c, CD68, CD207 (Langerin), CD300LF, S100B, fascin
Langerhans cell histiocytosis is negative to what immunohistochemical stain?
Negative: stabilin-1
in Non-Langerhans cell histiocytosis, how can you differentiate Systemic vs cutaneous?
This immunohistochemical staining is the most sensitive marker in detecting bircebk granules of langerhans cells
CD207, an antibody that recognizes a C-type lectin associated with Birbeck granules
In LCH, one of the most important predictors of outcome in patients with multiorgan involvement is how the disease responds to systemic treatment in the first how many weeks?
6 weeks
treatment protocol for LCH
**6-week **induction chemotherapy phase with:
1. vinblastine (6 mg/m2 weekly intravenous bolus) +
2. prednisolone (40 mg/m2 /day orally for 4 weeks and then tapered over 2 weeks)
and a subsequent therapy with vinblastine/prednisolone with or without mercaptopurine, depending on the treatment response after 6 weeks and the involvement of at-risk organs
induction treatment for LCH is done how many weeks?
6 weeks
represents a group of different disorders characterized by the proliferation of histiocytes that do not meet criteria to be diagnosed as Langerhans cells
NON-LANGERHANS CELL HISTIOCYTOSIS
N-LCH are immunohistochemically positive for?
(+) CD68
(-)S100B and CD1a
This can discriminate N-LCH from LCH and other granulomatous diseases
Stabilin-1 (formerly MS-1 antigen or MS-1-HMWP)
(+) for N-LCH
What are the subclassifications of cutaneous N-LCH?
- Juvenile Xanthogranuloma
- Adult xanthogranuloma
- Necrobiotic xanthogranuloma
- Spidle Cell N-LCH
Systemic forms of N-LCH are regarded as an accumulation of?
classically activated macrophages (Mφ1)
Mφ1 are known to develop in response to proinflammatory stimuli such as **T-helper (Th) 1 cytokines **(interferon-γ or bacterial products [lipopolysaccharides]).
They are characterized by secretion of proinflammatory cytokines, such as **interleukin (IL)-1, IL-6, and tumor necrosis factor-α, **and possess a strong oxidative burst and a profound antimicrobial activity.
Cutaneous N-LCH are characterized by the presence of
alternatively activated macrophages (Mφ2)
Mφ2 are induced by Th2 cytokines, including IL-4, IL-10, IL-13, and transforming growth factor-β, or by antiinflammatory mediators such as glucocorticoids.
They express antiinflammatory cytokines such as IL-1R antagonist and IL-10,chemokine receptor antagonists such as AMAC-1, broad-spectrum receptors of innate immunity, such as macrophage mannose receptor and the haptoglobin receptor CD163.
main clinical manifestation of Rosai-Dorfman disease (RDD)
Lymphadenopathy
The neck lymph nodes are the most common place of histiocyte accumulation, although accumulation outside of lymph nodes may occur
can be used as a serum marker to monitor disease progression or therapy response in Rosai-Dorfman disease (RDD)
S100B
The RDD cells are also positive for CD68, CD163, α1 -antitrypsin, α1 -antichymotrypsin, fascin, HAM-56 (human alveolar macrophage 56), and stabilin-1
hallmark of RDD
The hallmark of RDD is emperipolesis, in which different types of bone marrow cells, such as lymphocytes or neutrophils, are found in the cytoplasm of histiocytes with a background of mature lymphocytes and plasma cells.
characterized by persistent fever, splenomegaly with cytopenia, hypertriglyceridemia, and hypofibrinogenemia
Hemophagocytic lymphohistiocytosis (HLH)
Increased levels of various cytokines and soluble IL-2 receptor are biologic markers of HLH.
- Various cutaneous manifestations, such as erythroderma, generalized purpuric macules and papules, and morbilliform eruptions, have been described in up to 65% of HLH patients.
“CNS-risk” lesions
A risk factor for CNS involvement (25% risk) is LCH lesions of the facial bones or bones of the anterior or middle cranial fossae (“CNS-risk” lesions).
The most common manifestations of CNS involvement of LCH
**endocrine abnormalities **resulting from large pituitary tumors, most frequently diabetes insipidus, and neurodegenerative symptoms such as ataxia, dysarthria, cognitive dysfunction, and behavior changes
In children with LCH confined to the skin, what is the best management approach?
In children with LCH confined to the skin, a watch-and-wait strategy is the best approach
- Topical treatment can be tried with corticosteroid ointments, but topical steroids have shown little efficacy
- A skin rash that does not respond to topical steroids is considered a clue for LCH.
Based on the results of the most recent LCH-III trial, patients with multisystem LCH should be treated systemically for how many months?
12 months
systemic therapy for multisystem LCH
The treatment protocol consists of a 6-week induction chemotherapy phase with vinblastine (6 mg/m2 weekly intravenous bolus) combined with prednisolone (40 mg/m2 /day orally for 4 weeks and then tapered over 2 weeks) and a subsequent therapy with vinblastine/prednisolone with or without mercaptopurine, depending on the treatment response after 6 weeks and the involvement of at-risk organs
classifications of N-LCH
- Systemic
- Cutaneous
based on the algorithm of multisystem LCH, if there is involvement of high risk organs, what additional medication can you add to vinblastine and prednisolone?
Mercaptopurine
biologic markers of Hemophagocytic lymphohistiocytosis (HLH)
Increased levels of various cytokines and soluble IL-2 receptor
HLH is classified as one of the cytokine storm syndromes because high amounts of inflammatory cytokines are secreted.
- It is a benign, self-healing skin disorder that primarily affects infants younger than 1 year of age, but also can be found in older children
- usually manifests with both** solitary and multiple (oligolesional) papules or nodules **that are usually located on the **face, neck, and upper trunk, **and on other body parts, including lungs, bone, heart, and GI tract.
- Early lesions show a reddish-brown color
- Mature lesions have a reddish-yellow appearance
- Telangiectasia can be present
Juvenile xanthogranuloma (JXG)
- usually presents with small, yellow-red or yellow-brown, asymptomatic papules, located on the head and neck of young children with a tendency toward spontaneous remission
- Histologic examination of skin samples reveals an infiltrate of histiocytes, which closely approach the epidermis, accompanied by scattered lymphocytes and eosinophils.
- (+)CD68
Benign cephalic histiocytosis
- This rare disease is characterized by widespread, erythematous, essentially symmetrical papules, particularly involving proximal extremities as well as the trunk.
- Unlike in JXG, brownish papules and nodules do not develop; mucosal membranes, however, can be affected.
- Cutaneous lesions resolve spontaneously with remaining hyperpigmented maculae.
Generalized eruptive histiocytoma (GEH) of childhood
associated conditions with Juvenile xanthogranuloma
JXG is often accompanied with other disorders, such as** neurofibromatosis Type 1 and juvenile chronic myelogenous leukemia**
- characterized by multiple asymptomatic and symmetrically distributed brownish erythematous papules that involve the axial regions—trunk, face, and proximal extremities—that frequently evolve to flares.
- The big flexures are spared
- Mucous membranes were reported to be affected in some cases
- The papillary dermis is infiltrated by mostly small, nonlipidized cells and few lymphocytes underneath a Grenz zone, which is characteristic
- Macrophages are positive for CD68 and stabilin-1
GENERALIZED ERUPTIVE HISTIOCYTOMA
- Cutaneous lesions are firm, yellow-brownish papules or nodules that reach a size of several centimeters and progress slowly in size.
- The occurrence of lesions over the joints of fingers and wrist is typical
- usually appears around the age of 50 years
- twice as common in females
- Leonine facies can occur via confluence of facial lesions.
- Involvement of mucosae and conjunctivae can be appreciated in every second patient
Multicentric reticulohistiocytosis (MRH)
- rare disease with onset in middle age
* Long bone involvement is almost universal and is bilateral and symmetrical in nature - More than 50% of cases have some sort of extraskeletal involvement.
- This can include kidney, skin, brain, and lung involvement; less frequently, retro-orbital tissue, pituitary gland, and heart involvement is observed
- On the skin, xanthelasma and xanthoma are present in one-sixth of cases.
- Yellow-brown papular and widespread infiltrated lesions have been described in some patients
Erdheim-Chester disease
first-line treatment in Erdheim-Chester disease, as it has been clearly demonstrated to increase overall survival
Interferon-α
- It is a multisystem disease that affects** older adults **and it manifests as **yellowish plaques and nodules that can ulcerate. **
- predominantly located on the trunk, the extremities, and the face (periorbital lesions).
- Extracutaneous involvement also has been described, such as of the eyes, heart, skeletal muscle, larynx, spleen, and ovaries.
- There is an increased risk for concomitant hematologic and lymphoproliferative malignancies
Necrobiotic xanthogranuloma
A systemic association in the form of serum monoclonal gammopathy usually of what type is seen in 80% of necrobiotic xanthogranuloma patients?
immunoglobulin G κ and λ
- It is a rare, potentially autosomal dominant inherited disease.
- Progressive eruptions of self-resolving skin-colored to red-brown papules usually develop in the first decade on the nose, hands, forearms, and thighs
- These lesions can later develop into persistent and progressive erythematous papules
- Collections of epithelioid S100B/CD1a− and CD68 as well as weak stabilin-1+ histiocytes and telangiectatic vessels in the upper dermis of early lesions can be seen.
- In the mid-dermis of early and well-developed lesions, nodular aggregates of tightly packed spindle-shaped cells are present.
- Moderate to extensive **mucin production **was demonstrated in epithelioid histiocytes and spindle-shaped cells
Hereditary progressive mucinous histiocytosis
