71 Inflammatory and Malignant Histiocytosis Flashcards
Archaic term for tissue macrophages
Histiocyte
Dendritic Cell-related Histocytic disorders
Langerhans cell histiocytosis
Juvenile xanthogranuloma/Erdheim-Chester disease
Macrophage-Related Histiocytic Disorders
Hemophagocytic syndromes
Primary hemophagocytic lymphohistiocytosis
Secondary hemophagocytic syndromes
Rosai-Dorfman disease
Malignant Histiocytic Disorders
Monocyte-related leukemias
Extramedullary monocytic tumor (myeloid sarcoma)
Macrophage-related histiocytic sarcoma
Dendritic cell malignancy (malignant histiocytosis)
What mutations separate inflammatory neoplasias from hemophagocytic lymphohistiocytosis (HLH)
Recurrent mitogen-activated protein kinase (MAPK) pathway mutations
Hemophagocytic lymphohistiocytosis (HLH) is characterized by (monoconal or polyclonal) reactive macrophages
Polyclonal
Classification of histiocytic disorders based on clinical, histologic, and molecular features:
L group:
C group:
R Group:
M group:
H group:
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
Pathologic cluster designation of Langerhans cell histiocytosis
CD1a + /CD207 + DCs with rounded morphology
Its DC has abundant eosinophilic to amphophilic cytoplasm, and a nucleus that is kidney-shaped, deeply indented, or grooved (eg, reniform)
Langerhans cell histiocytosis
Recurrent mutations in MAPK pathway genes have been identified in more than____% of LCH lesions with BRAF V600E in over ____% of cases
80%
50%
BRAF V600E mutation can be detected by
Immunostain (VE1 antibody)
Polymerase chain reaction (PCR)
A type II transmembrane protein located on the cell surface of epidermal LC and is associated with formation of characteristic intracytoplasmic Birbeck granules
Langerin (CD207)
Immunophenotype of RDD
CD68 + /CD163 +
Characteristic finding in RDD
Emperipolesis (viable lymphocytes trafficking through cytoplasm)
Immunophenotype of JXG and ECD
CD68 + /CD163 + /Factor XIIIa + /CD1a – DCs
Characteristic finding in JXG and ECD
Abundant vacuoles that are described as foamy or lipid laden and stained with fascin
TRUE OR FALSE
Hemophagocytosis is characteristic and a required specific feature of HLH.
FALSE
Hemophagocytosis is characteristic, but neither a required nor specific feature of HLH.
Disease described in children with combinations of lytic bone lesions, skin and mucosal lesions, and diabetes insipidus
Hand-Christian-Schüller disease
Disease presentation in children as histiocytic infiltration of marrow, spleen, liver, and lung
Letterer-Siwe disease
Gene involved with Hispanic populations that was associated with increased risk of developing LCH
SMAD6
The only proven exposure increasing the risk of LCH, specifically in adults with pulmonary LCH
Cigarette smoking
Mutation in LCH associated with an increased risk of treatment failure and LCH-associated neurodegeneration.
BRAF V600E
The cell of origin of LCH
Epidermal LC
The most frequent presenting signs of LCH
Skin rashes and bone lesions
High-risk LHC organs
Liver, spleen, and marrow
A frequent presentation of LCH and looks like cradle cap in infants or severe dandruff in older children and adults
Seborrheic scalp rash
The most frequent site of LCH in children
Lytic lesion of the skull
One of the most serious complications of hepatic LCH
Cholestasis with sclerosing cholangitis
Seventy-five percent of children with sclerosing cholangitis will not respond to chemotherapy.
The typical chest radiograph of a patient with pulmonary LCH shows a ______________
Nonspecific interstitial infiltrate
The most frequent endocrine manifestation of LCH
Thickened pituitary stalk or mass with associated diabetes insipidus (DI)
The typical radiographic findings of neurodegenerative LCH
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
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
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
TRUE OR FALSE
In LCH, electron microscopy to identify Birbeck granules is typically necessary.
FALSE
Electron microscopy to identify Birbeck granules is not typically necessary.
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
BRAF V600E quantitative PCR
Therapy for limited skin LCH
Oral hydroxyurea, methotrexate, or thalidomide
Therapy for LCH with a single skull lesion of the frontal, parietal, or occipital bones, or single lesion of any other bone
Curettage only, or curettage plus injection of methylprednisolone
Therapy for LCH lesions affecting multiple bones
IV vinblastine and oral prednisone therapy for 12 months
Therapy for LCH patients with various combinations of skin, bone, lymph node, or pituitary gland disease
12 months of therapy with IV vinblastine and oral prednisone
Treatment for single-bone lesions of only the vertebrae or femoral neck that are at risk of collapse
Radiation therapy
Glucocorticoid injection
TRUE OR FALSE
CNS LCH lesions are frequently refractory to vinblastine and prednisone
TRUE
CNS LCH lesions are frequently refractory to vinblastine and prednisone
Options for refractory skin LCH
Oral hydroxyurea, thalidomide, or lenolidomide
Effective regimens for patients with recurrent bone disease
(1) IV cladribine
(2) IV cytarabine with or without vincristine
(3) IV clofarabine
MEK inhibitor
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.
Treatment-limiting toxicities of MEK inhibitors
Severe rash and eye inflammation, and second malignancy
Strategies No Longer Considered Effective in LCH
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.
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.
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.
Pathogenesis of LCH
activating MAPK pathway mutations
BRAF V600E mutation
NRAS and KRAS mutation
A presentation of LCH specific to adult
Isolated pulmonary LCH
LCH in adults is often similar to LCH in children, except that isolated adult pulmonary LCH is closely associated with_________________.
Smoking
The LCs in adult lung lesions are phenotypically similar to mature DCs and express high levels of the accessory molecules CD____ and CD___
CD80 and CD86
LCH bone involvement in adults includes more frequent lesions in____________ and fewer skull lesions compared with children
Mandible
IV cytarabine or IV cladribine
Effective for adults with skin, bone, lymph node, and (probably) pulmonary and mass lesions in the CNS.
IV cladribine
Front-line therapy for adults with LCH requiring systemic treatment
Cytarabine
TRUE OR FALSE
In adult LCH, extensive or mutilating surgery to remove skin lesions, teeth, or mandible or maxillary bones is not indicated.
TRUE
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
ERDHEIM-CHESTER DISEASE
TRUE OR FALSE
In ECD, the histiocytes are CD68 + /CD163 + /factor XIIIa + /CD1a − /S100 − and contain Birbeck granules
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
Most common clinical symptom in ECD
CNS symptoms (50%)
Fifty percent of patients have extraskeletal disease.
TRUE OR FALSE
In ECD, it is unusual for lymph nodes, liver, spleen, or axial skeleton to be affected
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
Most common CNS symptom in ECD
Cerebellar and pyramidal symptoms
Almost all ECD patients has this radiographic finding
Bilateral patchy osteosclerosis of the metaphysis and diaphysis of the femur, proximal tibia, and fibula
Other radiographic findings of ECD
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%
Were once considered the first-line treatments for ECD and may still be if inhibitor therapies are not available.
Subcutaneous IFN-α and pegylated IFN-α
Others:
Imatinib, cladribine, infliximab, tocilizumab, and anakinra
Vemurafenib
Cobimetinib
Drug that specifically targets activated BRAF monomers such as BRAF V600E
Vemurafenib
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
JUVENILE XANTHOGRANULOMA
Most common clinical presentation of JXG
Children younger than 2 years of age who have solitary skin nodules on their head, neck, or trunk
Three characteristic histologic patterns of JXG
Early JXG
Classic JXG
Transitional JXG
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
Early JXG
Exhibits abundant vacuolated, foamy histiocytes with Touton giant cells (lipid-laden histiocytes with multiple nuclei and a small amount of centrally oriented cytoplasm)
Classic JXG
Has a predominance of spindle-shaped cells resembling benign fibrous histiocytoma with foamy histiocytes and occasional giant cells
Transitional JXG
Treatment of JXG patients with a single or few lesions
No therapy, or an excisional biopsy can be done if desired for cosmetic reasons
Anoher name for Sinus histiocytosis with massive lymphadenopathy
Rosai-Dorfman disease (RDD)
Defined by accumulation of characteristic histiocytes in cervical lymph nodes, as well as other lymph nodes and/or extranodal sites
Rosai-Dorfman disease (RDD)
TRUE OR FALSE
RDD is usually self-limited
TRUE
RDD is usually self-limited, but may cause airway obstruction, orbital tumors, or CNS symptoms.
Most common extranodal site of RDD
Soft tissues of the head and neck
Sinuses or upper digestive tract
Germline mutations were identified in____________ in patients with familial RDD associated with histiocytosis-lymphadenopathy plus syndrome.
SLC29A3
The characteristic histologic feature of RDD
Dramatically expanded sinusoids and interfollicular regions by histiocytic cells with abundant amphophilic cytoplasm
Pathologic hallmark of histiocytes in RDD
Emperipolesis
The phenomenon of intact viable lymphocytes and plasma cells within cytoplasmic vacuoles passing through the histiocyte cytoplasm without damaging the transitory cells
Therapy for RDD
It is self-limited and does not require therapy although surgical excision may be considered for symptomatic treatment of local large lymph nodes.
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.
TRUE
In RDD, it is prudent to evaluate patients for associated malignancy or immune disorders, including autoimmune lymphoproliferative syndrome and IgG4-related disease.
Malignant Histiocytic Diseases
Histiocytic Sarcoma
Langerhans Cell Sarcoma
Interdigitating Dendritic Cell Sarcoma
Follicular Dendritic Cell Sarcoma
TRUE OR FALSE
In Malignant Histiocytic Diseases, females are affected more often than males and most patients had histiocytic sarcomas and LC sarcomas
FALSE
In Malignant Histiocytic Diseases, males are affected more often than females and most patients had histiocytic sarcomas and LC sarcomas
Histiocytic sarcoma represents less than 1% of all hemato-lymphoid neoplasms and is associated with a highly increased risk of developing ____________________
Non-Hodgkin lymphoma
Associated with prior or coincident diagnoses of Castleman disease, other malignancies, and autoimmune diseases
Follicular DC sarcomas
Most common presenting feature of Malignant Histiocytic Diseases
Lymphadenopathy
Malignant Histiocytic Diseases Prognostic score has 3 variables
- 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%.
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
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
A syndrome of pathologic immune activation that is often associated with genetic defects in cytotoxic lymphocyte function
Hemophagocytic lymphohistiocytosis (HLH)
Histopathologic finding of macrophages engulfing erythrocytes or other hematopoietic cells that can be found in marrow, lymph nodes, spleen, or liver biopsies
Hemophagocytic lymphohistiocytosis (HLH)
TRUE OR FALSE
Hemophagocytosis is not required for a diagnosis of HLH and is not specific to HLH.
TRUE
Hemophagocytosis is not required for a diagnosis of HLH and is not specific to HLH.
___________ HLH refers to children with a presumed or demonstrated inherited defect
Primary HLH
__________ HLH refers to children (or adults) who present with acquired immune dysregulation
Secondary HLH
Plays a central role in pathogenesis in mouse models of HLH
IFNγ
In HLH, this results in multiorgan dysfunction that can rapidly lead to death.
Hypercytokinemia
The most specific criterion for HLH
A pathogenic HLH-associated mutation
Frequent early clinical sign of HLH
Fever (91%)
Hepatomegaly (90%), splenomegaly (84%), neurological symptoms (47%), rash (43%), and lymphadenopathy (42%)
HLH is considered if a patient’s disease meets _____ of the eight criteria (HL-2004)
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)
Frequently used to screen for HLH
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
Test for HLH superior to testing NK cell function
Flow cytometry assays for degranulation assay CD107a and perforin
The most frequent infection associated with HLH and may not only reside in B cells but also in T and NK cells
EBV
HLH-94, frontline therapy for HLH is composed of
Combination of glucocorticoids with etoposide
Induction therapy with dexamethasone and etoposide, followed by continuous treatment with cyclosporine and pulses of dexamethasone and etoposide
Treatment for HLH with CNS symptoms or cerebrospinal fluid pleocytosis
Intrathecal methotrexate
Treatment for HLH with resistant disease, recurrent disease, or familial HLH
HCT
This is helpful for patients with highly elevated EBV viremia if EBV localizes to B cells.
Rituximab
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.
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.
A humanized antibody against IFNγ, recently received FDA approval for recurrent and refractory primary HLH
Emapalumab
HLH in the setting of persistent immune stimulation
Macrophage activation syndrome (MAS)
As many as ____% of patients with autoimmune disease have alterations of HLH-associated genes.
40%
