Histiocytic diseases

Question 1

Histiocytic disorders have ____ cell origins

Answer 1

dendritic

Question 2

Histiocytes differentiate from _____ precursors into ____ and several ___ lineages

Answer 2

CD34+, macrophages, DC

Question 3

Interstitial DC’s occur in _____ locations everywhere except the brain (but do in meninges)

Intraepithelial DC = ____ cells

In the dermis = ____ DC

(in the skin, epidermal = LC, dermal = dermal interstitial DC)

In the T-cell domain of lymphoid organs = ____ DC (both resident and migrating DC exist)

Answer 3

perivascular

Langerhans

Dermal

interdigitating

Question 4

5 cytokines and growth factors influencing DC’s?

Answer 4

FLT3 ligand

GM-CSF

TNF-a

IL4

TGF-b

Question 5

Macrophage differentiation from CD34+ precursors is activated by what 2 factors?

Answer 5

GM-CSF and M-CSF (macrophage-CSF)

Question 6

Blood monocytes become macrophages with M-CSF or DCs with what 2 factors?

Answer 6

GM-CSF + IL-4

Question 7

______ cells are the most important APCs for induction of response in naïve T cells

Answer 7

Dendritic

Question 8

DCs abundantly express ___, ____, _____ which all work to present antigen to T-cells

____ is exclusively expressed in skin DCs

Answer 8

CD1a, MHCI, MHCII

CD1a

Question 9

Beta-2 integrins CD11/18 are expressed differentially by all leukocytes

CD11c in ___ and _____

CD11b in ______ (and a subset of dermal interstitial DCs)

CD11d in ______

Answer 9

LC’s , interstitial DC

Macrophages

Splenic macrophages

Question 10

Differential expression of ____ and ____ differentiates LC’s and dermal interstitial DCs

LC are ____

DIDC are ____

Answer 10

E-cadherin, Thy-1 (CD90)

E-cadherin +, Thy-1 –

Thy-1 +

Question 11

DC migration occurs after antigen contact. They move to LN’s and connect with interdigitating DC’sDC to T-cell interaction involves orderly steps

B7 family CD80/86 appear on DC, and CD28 and CTLA-4 appear on T cells

Migrating T-cells upregulate MHC II and B7 costimulatory molecules to increase antigen presentation to T cells

vs in-situ DCs which express low MHC II and are better at antigen uptake

Question 12

Defective interactions between ____ and ____ appears to contribute to the development of reactive histiocytoses (cutaneous histiocytosis, systemic histiocytosis)

Answer 12

DC and T cells

Question 13

Histiocytic sarcoma generally derived from _____ that then rapidly disseminate

Answer 13

interstitial DCs

Question 14

What markers are only detectible in fresh smears or snap-frozen tissue (and not by flow):

Answer 14

CD1a, CD11b, CD11c, CD80, CD86

Question 15

It’s possible to presumptively identify histiocytes in FFPE tissues by combining CD18 (+), CD11d (+), Iba-1 (mac+, DC+), CD204 and 163 (macrophage >> DC)

Question 16

What is cutaneous histiocytoma?

Answer 16

Benign tumor of Langerhans cells

Question 17

Cutaneous histiocytoma presents as how many lesions?

Age of dogs

Most common neoplastic diagnosis in dogs ___ yr (__%)

Answer 17

Single lesion

Young dogs (<3)

<1yr (89%)

Question 18

Appearance of cutaneous histiocytoma?

Where does it commonly occur?

Answer 18

Solitary raised pink skin mass, usually on the cranial portion of the body

Question 19

Rapid growth with spontaneous regression in ____ , mediated by ____?

Avoid immunosuppression once acquired a definitive diagnosis

Answer 19

1-4months, CD8+ ab T lymphocytes

Question 20

Multiple, metastatic, or poorly differentiated cutaneous histiocytoma are usually classified as _____?

Answer 20

cutaneous LCH

Question 21

What is cutaneous langerhan cell histiocytosis (LCH)?

Answer 21

Multiple or diffuse cutaneous lesions of Langerhans Cells (LC) or LN metastasis

Question 22

Cutaneous LCH

Histologically how do these appear?

More common in what dog breed?

Regression may be delayed up to _____, and only regress in ___% of cases

1 report of improvement with ____

1 report of CR to ______

If solitary lesion with LN metastasis, better prognosis – remove surgically – with ____ survival

Answer 22

identical to histiocytoma

shar pei

10 months, 50%

CCNU

griseofulvin

1-4 years

Question 23

Reactive histiocytosis occurs where?

Age of dogs?

Common locations for lesions?

Answer 23

Cutaneous (benign diffuse aggregates of histiocytes that develops into nodules or plaques and crusts within the SQ)

tends to occur in younger dogs; history of allergic dermatitis is common (~50%)

Limited to skin and subcutis but multifocal, often on head, pinnae, limbs, scrotum

Can also occur on nasal planum and nasal cavity (clown nose)

Question 24

Reactive histiocytosis marker expression?

Answer 24

Activated interstitial DC: Cd1a+, CD1b+, CD1c+, CD11c+, MHC II+, Thy-1 +, CD4+, E-cadherin –

Question 25

How do you treat reactive histiocytosis?

Answer 25

Benign, responds to immunosuppression (systemic steroids), often requires maintenance therapy Steroids Steroids + tetracycline/doxy + niacinamide pred-azathioprine tetracycline + niacinamide +/- vitamin E, essential fatty acids

Question 26

What involves maintenance therapy for reactive histiocytosis?

Answer 26

tetracycline + niacinamide +/- vitamin E, essential fatty acids, or safflower oil cyclosporine + ketoconazole azathioprine azathioprine + pred pred

Question 27

How do you treat refractory cases of reactive histiocytosis?

Answer 27

Leflunomide + cyclosporine + ketoconazole Azathioprine

Question 28

Systemic (same staining pattern, origin; involves non-skin organs – subcutis, nasal epithelium, eyes, LN’s, bone marrow, spleen, liver, lung, mucus membranes) Familial in BMD, overrepresented also in Golden, Rottie, Irish Wolfhound Cx signs relate to organs affected Frequently reported anemia, monocytosis, lymphopenia, and occasional hypercalcemia Generally do not resolve spontaneously but may wax and wane Steroids alone not sufficient to control disease long-term azathioprine, leflunomide, cyclosporine may provide long-term control Rarely results in death but may result in euthanasia following recurrent flare-ups

Question 29

Dog breeds predisposed to histiocytic sarcoma?

Answer 29

BMD, but also flat-coated retriever (FCR), Rottwieler, mini schnauzer, Japan: Corgi

Question 30

What deletions in tumor suppressor genes are noted in canine HS?

Answer 30

Deletions in tumor suppressor genes CDKN2A/B, RB1, PTEN

Question 31

What gain of function mutation is noted in canine HS?

Answer 31

Gain-of-function mutation in PTPN11 (present in HS in 37% of BMD, 9% of other breeds)

Question 32

Flat coated retrievers more likely to have HS of the \_\_\_\_, ____ disease (7x increase likelihood vs BMD), and \_\_\_

Answer 32

forelimbs, localized disease, older

Question 33

Bernese Mountain Dog more likely ____ and ____ (2x increased likelihood vs FCR), _____ (7.7 vs 8.6yrs)

Answer 33

visceral, disseminated, younger

Question 34

What is Malignant histiocytosis?

Answer 34

old term that refers only to disseminated disease

Question 35

HS is the most common ____ tumor? ## Footnote CD18 __ (synovial cell sarcoma is \_\_) cytokeratin ___ (synovial cell sarcoma is \_\_\_) smooth muscle actin ___ (malignant fibrous histiocytoma is \_\_\_)

Answer 35

Periarticular Most common periarticular tumor in dogs (IHC to distinguish from synovial cell sarcoma) CD18 + (synovial cell sarcoma is -) cytokeratin – (synovial cell sarcoma is +) smooth muscle actin – (malignant fibrous histiocytoma is +)

Question 36

Histiocytic sarcoma are postiive for what two markers? Pan-monocyte marker ___ for HS diseases but cannot distinguish between histiocytic disorders Fresh or frozen tissue: CD1 (DC) or CD11 a-subunits (a, b, c, d) to distinguish cell of origin

Answer 36

CD18+, CD204+ Iba-1+

Question 37

What are common labwork abnormalities with HS?

Answer 37

anemia (regenerative), leukocytosis, thrombocytopenia, liver enzyme elevations, hypoalbuminemia, hypocholesterolemia, occasional hypercalcemia

Question 38

Most common cause of _____ in a retrospective 54-dog study

Answer 38

pancytopenia

Question 39

Histiocytic sarcoma ## Footnote Hyperferritinemia – may be due to tumor cell production of ferritin – but can also be seen in IMHA, liver disease, lymphoma

Question 40

What lung lobe is affected in HS?

Answer 40

R middle

Question 41

What is MST of periarticular form in comparison to toher forms? Dogs with no evidence of metastasis at diagnosis?

Answer 41

Periarticular form may have a better prognosis (MST 391 vs 128 days for all other locations) A study of 18 amputated localized periarticular HS found MST 6 mo, 91% metastasis Dogs with no evidence of metastasis at diagnosis do better– MST 980d (2.7 yr) vs 253d (8.4 mo)

Question 42

Skorupski 2007 retrospective 56 dogs: first report of CCNU efficacy 46% response rate, median remission duration 85d MST responders 172d; non-responders 60d Poor prognostic indicators: anemia, thrombocytopenia, hypoalbuminemia, splenic involvement, hemophagocytic phenotype

Question 43

Rasnick 2010 Phase II trial: 21 dogs (14 disseminated, 7 localized) treated @ 90mg/m2 RR 29% but 67% got only 1 dose Median response duration 96 days

Question 44

Skorupski 2009: 16 dogs with localized HS tx with CCNU adjuvant to local therapy 16 dogs, 15 with curative intent surgery, 1 with incisional bx and palliative (8gyx4) RT Median DFI 243d

Question 45

CCNU/DOX alternating q2weeks – RR 58%, Median TTP 185d Dacarbazine – rescue therapy – 18% response, event free survival 70d Epirubicin RR 29% Metrononic lomustine (Tripp JVIM 2011) -- Lomustine daily @ 2.84mg/m2 81 dogs (2 with HS); 22 discontinued d/t toxicity 4 dogs (6%) experienced PR, one of which was HS Metronomic chlorambucil (Leach JVIM 2011 – PUVTH) -- Chlorambucil @ 4mg/m2 36 dogs, 2 with HS -- PD in 1 dog, PR in 1 dog

Question 46

Hemophagocytic HS originates in the what cells?

Answer 46

Mac, not the DC

Question 47

Hemophagocytic histiocytic sarcoma involves what organs?

Answer 47

Invariably involves diffuse splenic infiltration… may also involve liver, marrow, LN, lung

Question 48

What are the common labwork abnormalities with hemophagocytic HS?

Answer 48

regenerative anemia (94%), thrombocytopenia (88%), hypoalbuminemia (94%), hypocholesterolemia (69%)

Question 49

Hemophagocytic HS is positive for what marker?

Answer 49

Confirmatory dx with histopath / stains – (CD11d+)

Question 50

Prognosis for dogs with HHS?

Answer 50

Aggressive and poor outcomes regardless of treatment – days to 1-2 months

Question 51

Cats with histiocytic disease have what type of disease?

Answer 51

Multifocal or disseminated disease

Question 52

3 common findings in cats with histiocytic sarcoma?

Answer 52

bone marrow involvement common in cats, as are severe anemia and thrombocytopenia

Question 53

Treatment for cats with histiocytic sarcoma?

Answer 53

Treatment not well studied – reported responses to CCNU, masitinib, and RT

Question 54

Feline progressive histiocytosis where does it originate?

Answer 54

Originates in skin DCs and progresses to other organs

Question 55

How does feline progressive histiocytosis appear in cats?

Answer 55

Multiple firm, haired or hairless, dermal papules or nodules with a predilection for head, feet, and legs

Question 56

What is the clinical course for feline progressive histiocytosis?

Answer 56

Usually progressive over months or years (median 13.4 months)

Question 57

Feline PH spreads to what areas?

Answer 57

Spreads to LN, lungs, abdominal viscera

Question 58

Feline progressive histiocytosis Gender predilection? Treatment?

Answer 58

Females over-represented Diagnosed via biopsy; IHC may be required to r/o other round cell tumors Surgery may be effective for early local control, but new lesions will develop Does not respond to steroids, and no reported effective therapy One report of spontaneous remission, one CR to masitinib, one CR to CCNU

Question 59

Pulmonary Langerhans Histiocytosis Single case series of 3 cats with Langerhans cell origin neoplasm Cats presented with hx respiratory distress or symptoms for 5 days to 7 months tRADS: diffuse, severe bronchointerstitial pattern with diffuse miliary to nodular opacities in all lung fields No response to therapy. Necropsy diagnosis based on presence of Birbeck’s granules Metastasis in all cases to LN, lungs, pancreas, kidneys, liver, and/or viscera

Question 60

Comparative aspects Histiocytic dz extremely rare in humans Presents in LN in 1/3, skin in 1/3, extranodal in 1/3 (intestinal with hepatosplenomegaly mostly) Humans present in advance stage (III or IV) and doesn’t respond to therapy Some cases have BRAF or MEK mutations Recent genomic comparative hybridization study suggested that dogs may be a good model for human HS