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

Disclosures

• No relevant financial relationships to disclose.

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

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

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

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

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

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

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-

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

PLCH Imaging: Atypical Manifestations

Nodules only (20%)

Basal predominant disease

Multifocal groundglassopacity; no cysts

Pulmonary hypertension: enlarged pulmonary arteries

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

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

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

ECD – PLCH Overlap

CD1a+ in PLCH cells

Factor XIII+ in ECD cells

Fibrohistiocytic pleural thickening

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

ECD: Typical Imaging Manifestations• Cardiopulmonary

ECD: Perivascular,

pericardial infiltration; tissue enhances may be FDG-avid

DIR-

FSPGR+

TIR

MDE/LGE

“coated aorta”

ECD: Typical Imaging Manifestations• Renal, perirenal

involvement: 33%

• CNS: diabetes insipidus, exopthalamos, orbital masses Perirenal infiltration: “hairy” kidney

Bilateral orbital enhancing masses

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

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.

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.

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

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

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

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

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

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

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

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

Presenting Author Contact

Clinton E. Jokerst, MD, Senior Associate Consultant, Radiology Mayo Clinic, Arizona5777 East Mayo Blvd.Phoenix, AZ 85054e-mail: jokerst.clinton@mayo.edu

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

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)