Los Angeles Society of

Pathologist Resident and

Fellow Symposium

Case Presentation

Winnie Wu, PGY4

May 14, 2013

Clinical History

50 year-old male with a history of recurrent pineal cavernous hemangioma, status post multiple resections (2005, 2007) as well as radiation (2004, 2007), presented in 2011 with new growth of a right parieto-occipital mass

MRI:

Post-contrast

T1-weighted

Enlarging 17 mm well-circumscribed, solidly-enhancing nodule adjacent to R lateral ventricle

Separate 3 mm enhancing focus

T1 and T2 hypo- to iso-intense

Avid enhancement after contrast injection, suggesting high N:C ratio

MRI:

T2-weighted

Moderate

perilesional

vasogenic edema

Mass effect on

ventricle

Right Parieto-Occipital

Gross Total Resection

Large Cells Negative For:

Pankeratin S100 Mart1 GFAP EMA CD45

CD3 CD20, PAX5 CD138 К/λ: no

restriction CD15 CD30 ALK CD56 EBV EBER

CD68

fascin

CD4

CD163

CD163+, CD68+, CD4+, fascin+ profile & morphology strongly suggested a histiocytic disorder

However, the differential included monocytic disorders

Lysozyme, CD117, CD34, MPO negative: unlikely monoblastic/monocytic or myelomonocytic sarcoma

Within the histiocytic disorders, the following were ruled out:

– CD1a, Langerin negative: unlikely Langerhans

– CD21, CD35, CD23 negative: unlikely follicular dendritic cells

– S100 negative: unlikely Rosai-Dorfman, interdigitating dendritic cells

– No hemophagocytosis: unlikely hemophagocytic d/o

– No xanthomatous Touton giant cells: unlikely spectrum of xanthogranulomatous d/o

Work-Up

overall Ki-67 labeling index was estimated at 15-20%

Infectious Work-Up

GMS and AFB negative

Adenovirus, CMV, and HSV I&II

immunohistochemical stains negative

46,Y,der(X)inv(X)(p11.2q24)t(X;18)(q24;q11.2)[7]

Abnormal clone (7/20) with pericentric inversion of chromosome X at

bands p11.2 and q24 & reciprocal translocation between chromosomes

Xq and 18q, which has not been reported as a consistent finding in solid

tumors

ish der(X)t(X;18)((q24;q11.2)(SYT+)

No rearrangement of the SYT gene-specific locus seen by metaphase

FISH with an 18q11.2 break-apart probe, ruling out synovial sarcoma

Final Diagnosis

Primary CNS histiocytic

sarcoma, presenting as a

post-radiation sarcoma

Swerdlow et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues 2008. (p355)

The Confusing History of Histiocytic Tumors

What Are Histiocytes?

Histiocytes are defined as:

Mononuclear cells derived from BM monocytes

High lysosomal content

Histiocytes include:

Macrophages: phagocytosis & antigen processing

Dendritic cells: non-phagocytic; antigen presentation & accessory support

Langerhans dendritic cells

Dermal dendritic cells

Interdigitating dendritic cells

Plasmacytoid dendritic cells

Follicular dendritic cells

http://nih.techriver.net/view.php?patientId=95

Macrophage

Lymph node sinuses, medullary cords, germinal centers

http://www.udel.edu/biology/Wags/histopage/colorpage/cly/clycmln.GIF

http://www.pathpedia.com/education/eatlas/histology/lymph_node/images.aspx

Langerhans Dendritic Cells

Epidermis & mucosa

When activated, home to

paracortical/T cell zone of

cutaneous draining lymph

nodes

CD1a in dermatopathic lymphadenitis

langerin

Ochoa et al. J Invest Dermatol. 2008; 128: 2225-31.

https://www.ipath-network.com/inctr/object/view/4264

Dermal Dendritic Cells

Ochoa et al. J Invest Dermatol. 2008; 128: 2225-31.

Papillary dermis

FXIIIa

Immature DC

phenotype (CD1b+)

Release

proinflammatory

cytokines

Antigen presentation

Interdigitating Dendritic Cells

Paracortex

Present

antigens to T-

cells

http://www.pathpedia.com/education/eatlas/histology/lymph_node/images.aspx

Follicular Dendritic Cells Primary & secondary follicles

Present antigens to B-cells

Long-living cells involved in immunologic/humoral memory

http://www.pathpedia.com/education/eatlas/histology/lymph_node/images.aspx

Plasmacytoid Dendritic Cells

Paracortex

Produce type-1 IFN's (IFNα)

Enhances NK–mediated cytotoxicity

Recruits macrophages

CD123

Colonna et al. Nat Immunol. 2004; 5: 1219-26.

CD45 Weak + Weak + + + - +

Swerdlow et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues 2008. (p355)

Ontogenic Classification of Histiocytic Disorders

Langerhans

cell histiocytosis

Interdigitating

dendritic cell

sarcoma

Blastic

plasmacytoid

dendritic cell

neoplasm

Follicular

dendritic cell

sarcoma

Acute

monocytic

leukemia

Hemophagocytic syndromes

Rosai-Dorfman Histiocytic sarcoma

Juvenile

xanthogranuloma

Swerdlow et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues 2008. (p354)

WHO 2008 Classification

Macrophage/histiocytic neoplasm

Histiocytic sarcoma

Dendritic cell neoplasms

Langerhans cell histiocytosis

Langerhans cell sarcoma

Interdigitating dendritic cell sarcoma

Follicular dendritic cell sarcoma

Fibroblastic reticular cell tumor

Indeterminate dendritic cell tumor

Dermal dendritic cells neoplasms

Disseminated juvenile xanthogranuloma

Classification of Histiocytic Disorders

Varied biological behavior

Dendritic cell-related

Langerhans cell histiocytosis

Secondary dendritic cell process

Juvenile xanthogranuloma

Solitary histiocytomas with dendritic cell phenotype

Macrophage-related

Hemophagocytic syndromes

Primary hemophagocytic lymphohistiocytosis

Secondary hemophagocytic syndromes

Rosai-Dorfman disease

Solitary histiocytoma with macrophage phenotype

Malignant

Monocyte-related

Extramedullary monocytic sarcoma

Acute monoblastic/monocytic leukemia (M5A, 5B)

AMML (M4)

AML with inv(16)

CMML

Dendritic cell-related histiocytic sarcoma

Langerhans cell sarcoma

Follicular dendritic cell sarcoma

Interdigitating dendritic cell sarcoma

Macrophage-related histiocytic sarcoma

1997 WHO Committee on Histiocytic/Reticulum Cell Proliferations & Reclassification Working Group of the Histiocyte Society

Histiocytic Sarcoma

WHO: malignant neoplasm of mature tissue histiocytes

Histopathology described in the literature is very similar to our current case

Importantly, histopathology not particularly distinctive - IHC & molecular studies essential

CNS Histiocytic Sarcoma

Differ morphologically from other sites

Neoplastic cells obscured by heavy inflammatory infiltrate of neutrophils, lymphocytes, plasma cells, with multiple foci of microabscess, fibrin, necrosis

Mimicks an inflammatory process

Criteria for Diagnosis

Requires >1 histiocytic marker

CD163: hemoglobin scavenger receptor, exclusively in monocytic/histiocytic lineage

Lysozyme, CD68, CD4, CD11c, CD14, α1-antichymotrypsin, α1-antitrypsin, MAC387, HAM56, Ki-M8, Ki-M4, cathespin D & E, M-CSF receptor Less specific

CD68: angiosarcoma, melanoma, granular cell tumor, carcinoma, some lymphomas, schwannoma, AML without monocytic differentiation, Langerhans cell tumor, juvenile xanthogranuloma, blastic plasmacytoid dendritic cell neoplasm, interdigitating dendritic cell proliferation

Criteria for Malignancy

1. Clonal cytogenetic abnormality

2. Aneuploidy

3. Monoclonality

4. Malignant morphology

5. High proliferative rate

6. Tumorigenicity

7. Aggressive clinical course

DDX: Other Hematopoeitic Neoplasms

Monoblastic/monocytic or myeloid sarcoma: myeloperoxidase, CD117, CD34

Primary DLBCL of CNS, T/histiocyte-rich large B-cell lymphoma: CD20, CD79a, PAX5, κ/λ, IgH rearrangement

Anaplastic large cell lymphoma: CD3, other T cell markers, CD30, ALK, TCRγ rearrangement, t(2;5) NPM/ALK

Pitfall: neoplastic cells may express CD68, CD11b, α1-antichymotrypsin, lysozyme

Peripheral T-cell lymphoma, lymphoepithelioid variant (Lennert lymphoma): CD3, CD8, CD56, cytotoxic granules, EBV+ Reed-Sternberg-like cells

Hodgkin lymphoma: Pax5, CD15, CD30

Plasma cell neoplasms: CD138, κ/λ

DDX: Other Histiocytic Disorders Dendritic cell disorders:

Langerhans cell neoplasms: CD1a, langerin, S100, Birbeck granules

Follicular dendritic cell sarcoma: CD21, CD35, CD23, clusterin, desmosomes & cytoplasmic processes by EM

Interdigitating dendritic cell sarcoma: S100, interdigitating cell processes by EM

Juvenile xanthogranuloma etc: pathognomonic Touton giant cells, FXIIIa, CD68, fascin

Erdheim-Chester: pathognomonic bilateral symmetrical osteosclerosis of metaphyses/diaphyses of long bones with sparing of epiphyses, lipid-laden foamy histiocytes, FXIIIa, CD68, fascin

Other macrophage disorders: Hemophagocytic syndromes: hemophagocytosis, clinical

(cytopenias, fever, ↑ spleen, ↑ triglyceride, ↓ fibrinogen, ↑ plasma soluble IL2 receptor)

Rosai-Dorfman: dural, emperipolesis, S100 Reticulohistiocytoma/sis: ground-glass histiocytes

DDX: Non-Hematopoeitic Neoplasms

Pleomorphic xanthoastrocytoma: characteristic imaging with circumscribed solid & cystic mass or a cyst with mural nodule, GFAP (100%), S100 (100%)

Pitfall: often CD68+

Gliosarcoma: areas of typical glioblastoma

Pitfall: sarcomatous area GFAP-

Lymphoplasma cell-rich meningioma: EMA, vimentin

Inflammatory myofibroblastic tumor: ALK, 2p23 rearrangement

Carcinoma: pan-cytokeratin, CAM5.2

Melanoma: S100, HMB45, melanA

DDX: Infectious, Inflammatory

Infection: viral inclusions, fungus, parasites/protozoa, microbiology workup

Mycobacterium avium-intracellulare spindle-cell pseudotumor: AFB

Subacute infarct: Red neurons, liquefactive necrosis

Tumefactive demyelination: Macrophages with Luxol fast blue/PAS+ myelin breakdown products

IgG4-related sclerosing disease: IgG4/IgG>40%, obliterative phlebitis

Idiopathic hypertrophic pachymeningitis

Inflammatory pseudotumor

Prognosis In general, poor prognosis: 60−80% die of progressive

disease within 1 year

Primary CNS HS also appears to have poor prognosis

6 total cases reported

5 cases:

Median survival 4.5 months

Metastases to serosal surfaces, mediastinum, bone

1 case: initial indolent course with response to resection & radiation, followed by subsequent relapse to the mediastinum 3½ years later

Current case: disease recurrence 1 year after resection & radiation, recurrent disease unresponsive to salvage chemotherapy

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Acknowledgements

Dr. Jonathan Said

Dr. Harry Vinters

Dr. Whitney Pope

Dr. W. Dean Wallace