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WILLIAM'S HEMATOLOGY > 71 Inflammatory and Malignant Histiocytosis > Flashcards

71 Inflammatory and Malignant Histiocytosis Flashcards

1
Q

Archaic term for tissue macrophages

A

Histiocyte

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2
Q

Dendritic Cell-related Histocytic disorders

A

Langerhans cell histiocytosis
Juvenile xanthogranuloma/Erdheim-Chester disease

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3
Q

Macrophage-Related Histiocytic Disorders

A

Hemophagocytic syndromes
Primary hemophagocytic lymphohistiocytosis
Secondary hemophagocytic syndromes
Rosai-Dorfman disease

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4
Q

Malignant Histiocytic Disorders

A

Monocyte-related leukemias
Extramedullary monocytic tumor (myeloid sarcoma)
Macrophage-related histiocytic sarcoma
Dendritic cell malignancy (malignant histiocytosis)

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5
Q

What mutations separate inflammatory neoplasias from hemophagocytic lymphohistiocytosis (HLH)

A

Recurrent mitogen-activated protein kinase (MAPK) pathway mutations

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6
Q

Hemophagocytic lymphohistiocytosis (HLH) is characterized by (monoconal or polyclonal) reactive macrophages

A

Polyclonal

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7
Q

Classification of histiocytic disorders based on clinical, histologic, and molecular features:

L group:
C group:
R Group:
M group:
H group:

A

L group: Langerhans cell histiocytosis, indeterminate cell histiocytosis, and Erdheim-Chester disease
C group: Juvenile xanthogranuloma
R Group: Rosai-Dorfman Disease
M group: Malignant histiocytic diseases
H group: Hemophagocytic lymphohistiocytic diseases

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8
Q

Pathologic cluster designation of Langerhans cell histiocytosis

A

CD1a + /CD207 + DCs with rounded morphology

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9
Q

Its DC has abundant eosinophilic to amphophilic cytoplasm, and a nucleus that is kidney-shaped, deeply indented, or grooved (eg, reniform)

A

Langerhans cell histiocytosis

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10
Q

Recurrent mutations in MAPK pathway genes have been identified in more than____% of LCH lesions with BRAF V600E in over ____% of cases

A

80%

50%

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11
Q

BRAF V600E mutation can be detected by

A

Immunostain (VE1 antibody)

Polymerase chain reaction (PCR)

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12
Q

A type II transmembrane protein located on the cell surface of epidermal LC and is associated with formation of characteristic intracytoplasmic Birbeck granules

A

Langerin (CD207)

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13
Q

Immunophenotype of RDD

A

CD68 + /CD163 +

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14
Q

Characteristic finding in RDD

A

Emperipolesis (viable lymphocytes trafficking through cytoplasm)

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15
Q

Immunophenotype of JXG and ECD

A

CD68 + /CD163 + /Factor XIIIa + /CD1a – DCs

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16
Q

Characteristic finding in JXG and ECD

A

Abundant vacuoles that are described as foamy or lipid laden and stained with fascin

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17
Q

TRUE OR FALSE

Hemophagocytosis is characteristic and a required specific feature of HLH.

A

FALSE

Hemophagocytosis is characteristic, but neither a required nor specific feature of HLH.

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18
Q

Disease described in children with combinations of lytic bone lesions, skin and mucosal lesions, and diabetes insipidus

A

Hand-Christian-Schüller disease

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19
Q

Disease presentation in children as histiocytic infiltration of marrow, spleen, liver, and lung

A

Letterer-Siwe disease

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20
Q

Gene involved with Hispanic populations that was associated with increased risk of developing LCH

A

SMAD6

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21
Q

The only proven exposure increasing the risk of LCH, specifically in adults with pulmonary LCH

A

Cigarette smoking

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22
Q

Mutation in LCH associated with an increased risk of treatment failure and LCH-associated neurodegeneration.

A

BRAF V600E

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23
Q

The cell of origin of LCH

A

Epidermal LC

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24
Q

The most frequent presenting signs of LCH

A

Skin rashes and bone lesions

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25
Q

High-risk LHC organs

A

Liver, spleen, and marrow

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26
Q

A frequent presentation of LCH and looks like cradle cap in infants or severe dandruff in older children and adults

A

Seborrheic scalp rash

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27
Q

The most frequent site of LCH in children

A

Lytic lesion of the skull

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28
Q

One of the most serious complications of hepatic LCH

A

Cholestasis with sclerosing cholangitis

Seventy-five percent of children with sclerosing cholangitis will not respond to chemotherapy.

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29
Q

The typical chest radiograph of a patient with pulmonary LCH shows a ______________

A

Nonspecific interstitial infiltrate

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30
Q

The most frequent endocrine manifestation of LCH

A

Thickened pituitary stalk or mass with associated diabetes insipidus (DI)

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31
Q

The typical radiographic findings of neurodegenerative LCH

A

Hyperintensity of the dentate nucleus and white matter of the cerebellum on T2-weighted MRI images, or hyperintense lesions of the basal ganglia on T1-weighted images, and atrophy of the cerebellum

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32
Q

TRUE OR FALSE

A biopsy of an affected organ is necessary to make the diagnosis of LCH with staining of the LCH lesion DCs with antibodies to CD207 and CD1a

A

TRUE

A biopsy of an affected organ is necessary to make the diagnosis of LCH with staining of the LCH lesion DCs with antibodies to CD207 and CD1a

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33
Q

TRUE OR FALSE

In LCH, electron microscopy to identify Birbeck granules is typically necessary.

A

FALSE

Electron microscopy to identify Birbeck granules is not typically necessary.

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34
Q

A sensitive method to detect LCH lesion cells as well as blood and marrow mononuclear cells that carry the mutation where allele burden may be lower than 0.1%

May become useful as a measure of disease burden in patients with high-risk disease treated with chemotherapy

A

BRAF V600E quantitative PCR

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35
Q

Therapy for limited skin LCH

A

Oral hydroxyurea, methotrexate, or thalidomide

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36
Q

Therapy for LCH with a single skull lesion of the frontal, parietal, or occipital bones, or single lesion of any other bone

A

Curettage only, or curettage plus injection of methylprednisolone

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37
Q

Therapy for LCH lesions affecting multiple bones

A

IV vinblastine and oral prednisone therapy for 12 months

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38
Q

Therapy for LCH patients with various combinations of skin, bone, lymph node, or pituitary gland disease

A

12 months of therapy with IV vinblastine and oral prednisone

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39
Q

Treatment for single-bone lesions of only the vertebrae or femoral neck that are at risk of collapse

A

Radiation therapy

Glucocorticoid injection

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40
Q

TRUE OR FALSE

CNS LCH lesions are frequently refractory to vinblastine and prednisone

A

TRUE

CNS LCH lesions are frequently refractory to vinblastine and prednisone

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41
Q

Options for refractory skin LCH

A

Oral hydroxyurea, thalidomide, or lenolidomide

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42
Q

Effective regimens for patients with recurrent bone disease

A

(1) IV cladribine
(2) IV cytarabine with or without vincristine
(3) IV clofarabine

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43
Q

MEK inhibitor

A

Cobimetinib

However, MAPK inhibition does not appear to clear mononuclear cells containing BRAF V600E from marrow or blood, as is observed in patients effectively treated with chemotherapy.

44
Q

Treatment-limiting toxicities of MEK inhibitors

A

Severe rash and eye inflammation, and second malignancy

45
Q

Strategies No Longer Considered Effective in LCH

A

Cyclosporine, anti-tumor necrosis factor (TNF) antibody, and interferon (IFN)-α

Extensive surgery is also not indicated.

Surgical resection or radiotherapy of groin or genital lesions is contraindicated because chemotherapy can heal skin lesions.

46
Q

TRUE OR FALSE

Patients with low-risk disease treated with vinblastine and prednisone have a 99% chance of survival, but more than 50% are not cured with initial therapy.

A

TRUE

Patients with low-risk disease treated with vinblastine and prednisone have a 99% chance of survival, but more than 50% are not cured with initial therapy.

47
Q

Pathogenesis of LCH

A

activating MAPK pathway mutations
BRAF V600E mutation

NRAS and KRAS mutation

48
Q

A presentation of LCH specific to adult

A

Isolated pulmonary LCH

49
Q

LCH in adults is often similar to LCH in children, except that isolated adult pulmonary LCH is closely associated with_________________.

A

Smoking

50
Q

The LCs in adult lung lesions are phenotypically similar to mature DCs and express high levels of the accessory molecules CD____ and CD___

A

CD80 and CD86

51
Q

LCH bone involvement in adults includes more frequent lesions in____________ and fewer skull lesions compared with children

A

Mandible

52
Q

IV cytarabine or IV cladribine

Effective for adults with skin, bone, lymph node, and (probably) pulmonary and mass lesions in the CNS.

A

IV cladribine

53
Q

Front-line therapy for adults with LCH requiring systemic treatment

A

Cytarabine

54
Q

TRUE OR FALSE

In adult LCH, extensive or mutilating surgery to remove skin lesions, teeth, or mandible or maxillary bones is not indicated.

A

TRUE

55
Q

Characterized by lipid-laden histiocytes with foamy or eosinophilic cytoplasm infiltrate bones and various organs and generate a fibroblastic response that leads to critical organ failure

A

ERDHEIM-CHESTER DISEASE

56
Q

TRUE OR FALSE

In ECD, the histiocytes are CD68 + /CD163 + /factor XIIIa + /CD1a − /S100 − and contain Birbeck granules

A

FALSE

In ECD, the histiocytes are CD68 + /CD163 + /factor XIIIa + /CD1a − /S100 − and do not contain Birbeck granules

The inflammatory infiltrate frequently includes Touton-like giant cells

57
Q

Most common clinical symptom in ECD

A

CNS symptoms (50%)

Fifty percent of patients have extraskeletal disease.

58
Q

TRUE OR FALSE

In ECD, it is unusual for lymph nodes, liver, spleen, or axial skeleton to be affected

A

TRUE

It is unusual for lymph nodes, liver, spleen, or axial skeleton to be affected, whereas these areas are frequently affected in LCH and RDD

59
Q

Most common CNS symptom in ECD

A

Cerebellar and pyramidal symptoms

60
Q

Almost all ECD patients has this radiographic finding

A

Bilateral patchy osteosclerosis of the metaphysis and diaphysis of the femur, proximal tibia, and fibula

61
Q

Other radiographic findings of ECD

A

Perirenal infiltration, extending through the fat of the anterior or posterior pararenal spaces, leading to the classic “hairy kidney” appearance (>60%)
Circumferential sheathing of the aorta (>60%), Retroperitoneal fibrosis-like infiltrates (20%

62
Q

Were once considered the first-line treatments for ECD and may still be if inhibitor therapies are not available.

A

Subcutaneous IFN-α and pegylated IFN-α

Others:
Imatinib, cladribine, infliximab, tocilizumab, and anakinra
Vemurafenib
Cobimetinib

63
Q

Drug that specifically targets activated BRAF monomers such as BRAF V600E

A

Vemurafenib

64
Q

A histiocytic disorder that affects the skin with multiple nodules in the head, neck, and trunk primarily in children, although adults can also be affected

A

JUVENILE XANTHOGRANULOMA

65
Q

Most common clinical presentation of JXG

A

Children younger than 2 years of age who have solitary skin nodules on their head, neck, or trunk

66
Q

Three characteristic histologic patterns of JXG

A

Early JXG
Classic JXG
Transitional JXG

67
Q

Characterized by small- to intermediatesize mononuclear histiocytes, have only small quantities of lipid in the cytoplasm and Touton-type giant cells are absent; has relatively more mitoses but there is no cytologic atypia

A

Early JXG

68
Q

Exhibits abundant vacuolated, foamy histiocytes with Touton giant cells (lipid-laden histiocytes with multiple nuclei and a small amount of centrally oriented cytoplasm)

A

Classic JXG

69
Q

Has a predominance of spindle-shaped cells resembling benign fibrous histiocytoma with foamy histiocytes and occasional giant cells

A

Transitional JXG

70
Q

Treatment of JXG patients with a single or few lesions

A

No therapy, or an excisional biopsy can be done if desired for cosmetic reasons

71
Q

Anoher name for Sinus histiocytosis with massive lymphadenopathy

A

Rosai-Dorfman disease (RDD)

72
Q

Defined by accumulation of characteristic histiocytes in cervical lymph nodes, as well as other lymph nodes and/or extranodal sites

A

Rosai-Dorfman disease (RDD)

73
Q

TRUE OR FALSE

RDD is usually self-limited

A

TRUE

RDD is usually self-limited, but may cause airway obstruction, orbital tumors, or CNS symptoms.

74
Q

Most common extranodal site of RDD

A

Soft tissues of the head and neck
Sinuses or upper digestive tract

75
Q

Germline mutations were identified in____________ in patients with familial RDD associated with histiocytosis-lymphadenopathy plus syndrome.

A

SLC29A3

76
Q

The characteristic histologic feature of RDD

A

Dramatically expanded sinusoids and interfollicular regions by histiocytic cells with abundant amphophilic cytoplasm

77
Q

Pathologic hallmark of histiocytes in RDD

A

Emperipolesis

The phenomenon of intact viable lymphocytes and plasma cells within cytoplasmic vacuoles passing through the histiocyte cytoplasm without damaging the transitory cells

78
Q

Therapy for RDD

A

It is self-limited and does not require therapy although surgical excision may be considered for symptomatic treatment of local large lymph nodes.

79
Q

TRUE OR FALSE

In RDD, it is prudent to evaluate patients for associated malignancy or immune disorders, including autoimmune lymphoproliferative syndrome and IgG4-related disease.

A

TRUE

In RDD, it is prudent to evaluate patients for associated malignancy or immune disorders, including autoimmune lymphoproliferative syndrome and IgG4-related disease.

80
Q

Malignant Histiocytic Diseases

A

Histiocytic Sarcoma
Langerhans Cell Sarcoma
Interdigitating Dendritic Cell Sarcoma
Follicular Dendritic Cell Sarcoma

81
Q

TRUE OR FALSE

In Malignant Histiocytic Diseases, females are affected more often than males and most patients had histiocytic sarcomas and LC sarcomas

A

FALSE

In Malignant Histiocytic Diseases, males are affected more often than females and most patients had histiocytic sarcomas and LC sarcomas

82
Q

Histiocytic sarcoma represents less than 1% of all hemato-lymphoid neoplasms and is associated with a highly increased risk of developing ____________________

A

Non-Hodgkin lymphoma

83
Q

Associated with prior or coincident diagnoses of Castleman disease, other malignancies, and autoimmune diseases

A

Follicular DC sarcomas

84
Q

Most common presenting feature of Malignant Histiocytic Diseases

A

Lymphadenopathy

85
Q

Malignant Histiocytic Diseases Prognostic score has 3 variables

A
  • Elevated lactate dehydrogenase
  • Eastern Cooperative Oncology Group performance status 2–4,
  • Ann Arbor stage 3–4

The survival at 30 months for patients with low-risk disease (1 of 3 findings) was 80% and for those with intermediate risk disease (2 of 3 findings) was 30%.

86
Q

TRUE OR FALSE

MALIGNANT FIBROUS HISTIOCYTOMA AND GIANT-CELL TUMOR OF THE BONE are not derived from histiocytes, but are poorly differentiated fibrosarcomas, myosarcomas, fibromyxosarcomas, or liposarcomas

A

TRUE

MALIGNANT FIBROUS HISTIOCYTOMA AND GIANT-CELL TUMOR OF THE BONE are not derived from histiocytes, but are poorly differentiated fibrosarcomas, myosarcomas, fibromyxosarcomas, or liposarcomas

87
Q

A syndrome of pathologic immune activation that is often associated with genetic defects in cytotoxic lymphocyte function

A

Hemophagocytic lymphohistiocytosis (HLH)

88
Q

Histopathologic finding of macrophages engulfing erythrocytes or other hematopoietic cells that can be found in marrow, lymph nodes, spleen, or liver biopsies

A

Hemophagocytic lymphohistiocytosis (HLH)

89
Q

TRUE OR FALSE

Hemophagocytosis is not required for a diagnosis of HLH and is not specific to HLH.

A

TRUE

Hemophagocytosis is not required for a diagnosis of HLH and is not specific to HLH.

90
Q

___________ HLH refers to children with a presumed or demonstrated inherited defect

A

Primary HLH

91
Q

__________ HLH refers to children (or adults) who present with acquired immune dysregulation

A

Secondary HLH

92
Q

Plays a central role in pathogenesis in mouse models of HLH

A

IFNγ

93
Q

In HLH, this results in multiorgan dysfunction that can rapidly lead to death.

A

Hypercytokinemia

94
Q

The most specific criterion for HLH

A

A pathogenic HLH-associated mutation

95
Q

Frequent early clinical sign of HLH

A

Fever (91%)

Hepatomegaly (90%), splenomegaly (84%), neurological symptoms (47%), rash (43%), and lymphadenopathy (42%)

96
Q

HLH is considered if a patient’s disease meets _____ of the eight criteria (HL-2004)

A

5

  • Fever
  • Splenomegaly
  • Cytopenias in at least 2 cell lines:
    Hemoglobin < 90 g/L
    Platelets < 100 × 109/L
    Neutrophils < 1 × 109//L
  • Hypertriglyceridemia and/or hypofibrinogenemia:
    Fasting triglycerides >3 mmol/L (>265 mg/dL)
    Fibrinogen <1.5 g/L
  • Hemophagocytosis in marrow or spleen or lymph nodes
  • Low or absent activity of NK cells
  • Ferritin > 500 mcg/L
  • Soluble CD25 (soluble interleukin-2 receptor) >2 400 U/mL (or 2 SD above normal for age)
97
Q

Frequently used to screen for HLH

A

Ferritin

A ferritin level higher than 500 mcg/L is one of the HLH-2004 inclusion criteria and is likely overly sensitive for a diagnostic criterion

98
Q

Test for HLH superior to testing NK cell function

A

Flow cytometry assays for degranulation assay CD107a and perforin

99
Q

The most frequent infection associated with HLH and may not only reside in B cells but also in T and NK cells

A

EBV

100
Q

HLH-94, frontline therapy for HLH is composed of

A

Combination of glucocorticoids with etoposide

Induction therapy with dexamethasone and etoposide, followed by continuous treatment with cyclosporine and pulses of dexamethasone and etoposide

101
Q

Treatment for HLH with CNS symptoms or cerebrospinal fluid pleocytosis

A

Intrathecal methotrexate

102
Q

Treatment for HLH with resistant disease, recurrent disease, or familial HLH

A

HCT

103
Q

This is helpful for patients with highly elevated EBV viremia if EBV localizes to B cells.

A

Rituximab

104
Q

TRUE OR FALSE

Adult patients more frequently have HLH driven by malignancy or another persistent immune trigger and may not respond as well to HLH-94 therapy.

A

TRUE

Adult patients more frequently have HLH driven by malignancy or another persistent immune trigger and may not respond as well to HLH-94 therapy.

105
Q

A humanized antibody against IFNγ, recently received FDA approval for recurrent and refractory primary HLH

A

Emapalumab

106
Q

HLH in the setting of persistent immune stimulation

A

Macrophage activation syndrome (MAS)

107
Q

As many as ____% of patients with autoimmune disease have alterations of HLH-associated genes.

A

40%

WILLIAM'S HEMATOLOGY (109 decks)

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