Non-Malignant Histiocytic Disorders of the Thorax: Typical ...
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Non-Malignant Histiocytic Disorders of the Thorax: Typical
and Variant Presentations
Clinton E. Jokerst MD, Maxwell L. Smith MD, Prasad M. Panse MD, Kristopher W. Cummings MD,
Eric A. Jensen MD, Michael B. Gotway MD
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Disclosures
• No relevant financial relationships to disclose.
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Learning Objectives / Outcomes• Review the genesis and classification of non-
malignant histiocytic disorders affecting the thorax
• Illustrate histopathological, immunohistochemical, and typical / atypical imaging findings of these disorders
• Enumerate imaging features that allow diagnosis of these disorders
• Target audience: general radiologists, imaging trainees
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Histiocytoses• Rare disorders characterized by accumulation of
macrophage, dendritic, or monocyte-derived cells• ˃100 subtypes described • Histiocytes: Immune cell group including macrophages &
dendritic cells Histiocyte is a tissue-resident macrophage
• Mononuclear phagocyte system: dendritic cells (DC), monocytes, macrophages DCs: non-phagocytic; present antigens, activate T
cells; classified / sub-classified by immunohistochemical expression; Langerhans cell (LC) is DC subtype
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Histiocytoses• Previously classified into 3 categories:1,2
Langerhans cell histiocytosis (LCH) Non-Langerhans cell related histiocytosis malignant histiocytoses
• Also previously classified as 1° or 2° depending on whether causative insult known;2 further categorized based on whether histiocytic proliferation is a majoror minor component of histopathologic findings
• Recent insights regarding histology, phenotype, molecular alterations, clinical manifestations, & imaging presentations has prompted revised classification1
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Histiocytoses: Revised Classification
L Group
C Group
R Group
M Group
H Group
Langerhanscell
histiocytosis (LCH)
Indeterminatecell
histiocytosis
Erdheim-Chester
Disease (ECD)
Rosai-DorfmanDisease (RDD)
1° or 2°malignant histiocytosis
Monogenic inherited conditions leading to hemophagocytic
lymphohistiocytosis
Others
Juvenile or adult xanthogranuloma
Solitary reticulohistiocytoma
Benign cephalic histiocytosis
Generalized eruptive histiocytosis
Progressive nodular histiocytosis
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Langerhans Cell Histiocytosis• Proliferation/infiltration of LCs in ≥ 1 organ Older terms: eosinophilic granuloma, histiocytosis X LC multisystemic syndromes (typically affect children):
Letterer-Siwe, Hand-Schűller-Christian, Hashimoto-Pritzker
• Pulmonary LCH:1 As part of systemic disease: typically children, not
smoking-related; clonal neoplasm Isolated: Most commonly affects lung Non-neoplastic; adults, 20-40 years old, smokers Abnormal immune response to cigarette smoke
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PLCH: Histopathology• Pathology depends on disease phase;
all show background smoking changes (RB, SRIF)
• Proliferative phase Cellular airway
centered nodules & cysts
*
Centrilobular nodule (airway) Cyst with cell proliferation
Background RB; SRIF Mixed inflammation, eosinophils, giant cells, smoker’s macrophages & numerous hallmark LCs
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CD1a+
PLCH: Histopathology, cont.• Fibrotic phase centrilobular stellate scars less frequent to absent LC
Stellate scars in fibrotic phase
LC with eosinophils & giant cells
S-100 IHC
• Hallmark cell histiocytes with crumpled
tissue paper or coffee bean-shaped nuclei
• EM: Birbeck granule (not used in practice) LC immunostaining: CD1a+, CD207+, CD68+
S-100+, Factor XIII-
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PLCH Imaging: Typical Manifestations
“Bizarre”-shaped cysts
End – stage diseaseresembling severe
emphysema
Pneumothorax
*
Larger Nodules
Upper lobe predominant centrilobular nodules, cysts, cavities
Limited Disease Extensive Disease
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PLCH Imaging: Atypical Manifestations
Nodules only (20%)
Basal predominant disease
Multifocal groundglassopacity; no cysts
Pulmonary hypertension: enlarged pulmonary arteries
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Erdheim-Chester Disease (ECD)• Histopathology overlaps with LCH: up to 20% with
ECD have LC lesions, and both disorders have clonal mutations of MAPK pathway in > 80%1
• Mean age: 55 – 60 years; ♂:♀ = 3:11
• Classification:1,2
Classical ECD without bone involvement Associated with myleoproliferative disorder Extra-cutaneous / disseminated JXG with MAPK-
activating mutation or ALK translocation
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ECD: Histopathology• Unique pattern of pleural and septal fibrosis• Sharp transition to alveolar parenchyma• Dense fibrosis with nodules of inflammation
Pleural & septalfibrosis with
sharp demarcations &
inflammation
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Factor XIII+
ECD: Histopathology, cont.• Embedded
xanthoumatous or “foamy” mononucleatedhistiocytes with small nuclei
• Rare Touton cells• ECD histiocytes:
CD68+, CD163+, Factor XIII+
• CD1a-
Touton cells
Foamy histiocytes embedded in fibrosis
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ECD – PLCH Overlap
CD1a+ in PLCH cells
Factor XIII+ in ECD cells
Fibrohistiocytic pleural thickening
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ECD: Typical Imaging Manifestations• >95% osseous involvement
(metaphyseal, diaphysealcortical sclerosis)
• 50% cardiopulmonary: Smooth interlobular septal
thickening Pericardial, pleural infiltration
Cardiomegaly,septal thickening*
**
Pericardialand pleural effusions
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ECD: Typical Imaging Manifestations• Cardiopulmonary
ECD: Perivascular,
pericardial infiltration; tissue enhances may be FDG-avid
DIR-
FSPGR+
TIR
MDE/LGE
“coated aorta”
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ECD: Typical Imaging Manifestations• Renal, perirenal
involvement: 33%
• CNS: diabetes insipidus, exopthalamos, orbital masses Perirenal infiltration: “hairy” kidney
Bilateral orbital enhancing masses
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ECD: Pre- & Post-Treatment
• Current Rx: corticosteroids, inferferon-alpha, chemotherapy, radiation3
• V600EBRAF mutation in 50%: implies BRAF kinase inhibitor therapy may be effective3,4
* *
Interval reduction in pleural and pericardial effusions, with clinical
improvement, after cladribine therapy
Pre-Rx
Post-Rx
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ECD: Atypical Imaging Manifestations• Absence 1 or
more “typical” features (perirenal, aortic infiltration, osteosclerosis)
• LCH – like lesions
Biopsy-proven ECD: cysts, some clustered, more suggestive of LCH, peribronchial & subpleural masses ? IgG-4 disease. Typical
osseous, periaortic & perirenal lesions were absent.
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ECD: Atypical Imaging Manifestations
Biopsy-proven ECD: centrilobular nodules,nodular perivascular thickening, faintly
nodular septal thickening, & ground-glass opacity. Typical osseous, periaortic &
perirenal lesions are absent.
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Cutaneous Non-LC Histiocytosis1
• “C” group lesions: cutaneous & mucocutaneous histiocytosis
• May be associated with systemic involvement• Juvenile xanthogranuloma most common of
this group• Non-juvenile xanthogranulomatous lesions in
this group include cutaneous Rosai-Dorfman disease, necrobiotic xanthogranuloma (may be associated with myeloma) & multicentric reticulohistiocytosis
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Cutaneous Non-LCH: Histopathology, Clinical, & Imaging
• S100-, CD1a-
• Imaging expressions rare: micronodules & larger nodules, up to 25 mm, reported
• A sarcoid-like appearance may occur5
Clustered nodules along the bronchovascular bundles & fissures resembling sarcoid,
successfully treated with methotrexate
2016
2014
2015
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Rosai-Dorfman Disease (RDD)1
• aka Sinus histiocytosis with massive lymphadenopathy
• Primarily disorder of children, young adults, affecting lymph nodes
• Most commonly presents as bilateral, painless, cervical lymphadenopathy
• Extranodal involvement (43%): Skin, nasal cavity, bone, soft tissue, retro-orbital
tissue CNS: pachymeningitis
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RDD: Histopathology• Fibrohistiocytic expansion of the pleura, septum, &
bronchovascular bundles
Lymphoid follicles
Fibro-inflammatory pleural & bronchovascular bundle
expansion
• Background of moderate mixed inflammatory cell infiltrate
• Lymphoid follicles
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RDD: Histopathology• Nodules & aggregates of
histiocytes, mixed background inflammation S100+, CD68+, CD14+, CD163+
CD1a-, CD207-
histiocytes engulf erythrocytes, plasma cells, lymphocytes= emperipolesis
Histiocytes with emperipolesis S100+ histiocytes
Histiocytes with inflammation
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RDD: Histopathology• Background moderate mixed inflammatory cell infiltrate numerous plasma cells, may be IgG+; ddx= IgG4 dz6
Dense bronchovascular inflammation
S-100+ histiocytes(light brown)
IgG4+ plasma cells in background
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RDD: Imaging Manifestations• Thoracic
involvement may be more common than previously recognized7: Mediastinal,
peribronchial lymph node enlargement “Interstitial” disease
(NSIP-like) Pleural effusion FDG-avid
Pt. with headache; MR shows pachymeningitis. Pre- brain biopsy
testing prompted thoracic CT & FDG-PET. Brain and bronchoscopic
biopsy confirmed RDD
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Thoracic Histiocytoses2
LCH ECD RDD
Histology & Immunohistochemistry
CD1a+
CD68+
CD207+
S100+
Factor XIIIa-
CD68+
CD163+
CD1a-
Factor XIIIa+
S100+
CD1a-
CD68+
Factor XIIIa-
Imaging
upper lobenodules, cysts emphysema
periaortic, perinrenalinfiltrationseptal thickeningosteosclerosispleural, pericardial effusion
Mediastinal, peribronchial lymph node enlargement“interstitial” disease
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Presenting Author Contact
Clinton E. Jokerst, MD, Senior Associate Consultant, Radiology Mayo Clinic, Arizona5777 East Mayo Blvd.Phoenix, AZ 85054e-mail: [email protected]
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References1. Emile JF, Abla O, Fraitag S, Horne A, Haroche J, Donadieu J, Requena-Caballero L, Jordan
MB, Abdel-Wahab O, Allen CE, Charlotte F, Diamond EL, Egeler RM, Fischer A, Herrera JG, Henter JI, Janku F, Merad M, Picarsic J, Rodriguez-Galindo C, Rollins BJ, Tazi A, Vassallo R, Weiss LM; Histiocyte Society. Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages. Blood 2016(2); 127(22):2672-2681.
2. Ahuja J, Kanne JP, Meyer CA, Pipivath SNJ, Schmidt RA, Swanson JO, Godwin JD. Histiocytic disorders of the chest: imaging findings. RadioGraphics 2015; 35:357-337.
3. Abla O, Weitzman S. Treatment of Langerhans cell histiocytosis: role of BRAF/MAPK inhibition. Hematology Am Soc Hematol Educ Program 2015; 2015:565-570.
4. Azadeh N, Tazelaar HD, Gotway MB, Mookadam F, Fonseca R. Erdheim-Chester disease treated successfully with cladribine. Resp Med Case Report 2016; 18:37-40.
5. Lloyd CR, Nicholson AG, Wells AU, Hansell DM. Non Langerhans Histiocytosis HRCT J Thorac Imag 2010; 25:W133-135.
6. Apperley ST, Hyjek EM, Musani R, Thenganatt J. Intrathoracic Rosai Dorfman disease with focal aggregates of IgG4-bearing plasma cells: case report and literature review Ann Am Thorac Soc 2016; 13(5):666-670
7. Cartin-Ceba R, Golbin JM, Yi ES, Prakash UBS, Vassallo R. Intrathoracic manifestations of Rosai-Dorfman disease. Respir Med 2010; 104:1344-1349.
Histicytosis organization: https://histio.org/sslpage.aspx?pid=291
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Histiocytoses: Revised Classification• L (Langerhans) Group: LCH, Indeterminate cell
histiocytosis (ICH), Erdheim-Chester disease (ECD) • C Group: cutaneous non-LCH, juvenile
xanthogranuoma, adult xanthogranuloma, solitary reticulohistiocytoma, benign cephalic histiocytosis, generalized eruptive histiocytosis, & progressive nodular histiocytosis
• R Group: Rosai-Dorfman disease (RDD)• M Group: 1° malignant histiocytosis, 2° to or following
other hematologic malignancy• H Group: Monogenic inherited conditions leading to
hemophagocytic lymphohistiocytosis (HLH)