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Histiocytic diseases Flashcards

1
Q

Histiocytic disorders have ____ cell origins

A

dendritic

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2
Q

Histiocytes differentiate from _____ precursors into ____ and several ___ lineages

A

CD34+, macrophages, DC

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3
Q

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)

A

perivascular

Langerhans

Dermal

interdigitating

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4
Q

5 cytokines and growth factors influencing DC’s?

A

FLT3 ligand

GM-CSF

TNF-a

IL4

TGF-b

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5
Q

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

A

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

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6
Q

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

A

GM-CSF + IL-4

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7
Q

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

A

Dendritic

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8
Q

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

____ is exclusively expressed in skin DCs

A

CD1a, MHCI, MHCII

CD1a

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9
Q

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 ______

A

LC’s , interstitial DC

Macrophages

Splenic macrophages

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10
Q

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

LC are ____

DIDC are ____

A

E-cadherin, Thy-1 (CD90)

E-cadherin +, Thy-1 –

Thy-1 +

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11
Q

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

A
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12
Q

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

A

DC and T cells

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13
Q

Histiocytic sarcoma generally derived from _____ that then rapidly disseminate

A

interstitial DCs

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14
Q

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

A

CD1a, CD11b, CD11c, CD80, CD86

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15
Q

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

A
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16
Q

What is cutaneous histiocytoma?

A

Benign tumor of Langerhans cells

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17
Q

Cutaneous histiocytoma presents as how many lesions?

Age of dogs

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

A

Single lesion

Young dogs (<3)

<1yr (89%)

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18
Q

Appearance of cutaneous histiocytoma?

Where does it commonly occur?

A

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

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19
Q

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

Avoid immunosuppression once acquired a definitive diagnosis

A

1-4months, CD8+ ab T lymphocytes

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20
Q

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

A

cutaneous LCH

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21
Q

What is cutaneous langerhan cell histiocytosis (LCH)?

A

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

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22
Q

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

A

identical to histiocytoma

shar pei

10 months, 50%

CCNU

griseofulvin

1-4 years

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23
Q

Reactive histiocytosis occurs where?

Age of dogs?

Common locations for lesions?

A

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)

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24
Q

Reactive histiocytosis marker expression?

A

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

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25
Q

How do you treat reactive histiocytosis?

A

Benign, responds to immunosuppression (systemic steroids), often requires maintenance therapy

Steroids

Steroids + tetracycline/doxy + niacinamide

pred-azathioprine

tetracycline + niacinamide +/- vitamin E, essential fatty acids

26
Q

What involves maintenance therapy for reactive histiocytosis?

A

tetracycline + niacinamide +/- vitamin E, essential fatty acids, or safflower oil

cyclosporine + ketoconazole

azathioprine

azathioprine + pred

pred

27
Q

How do you treat refractory cases of reactive histiocytosis?

A

Leflunomide + cyclosporine + ketoconazole

Azathioprine

28
Q

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

A
29
Q

Dog breeds predisposed to histiocytic sarcoma?

A

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

30
Q

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

A

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

31
Q

What gain of function mutation is noted in canine HS?

A

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

32
Q

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

A

forelimbs, localized disease, older

33
Q

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

A

visceral, disseminated, younger

34
Q

What is Malignant histiocytosis?

A

old term that refers only to disseminated disease

35
Q

HS is the most common ____ tumor?

CD18 __ (synovial cell sarcoma is __)

cytokeratin ___ (synovial cell sarcoma is ___)

smooth muscle actin ___ (malignant fibrous histiocytoma is ___)

A

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 +)

36
Q

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

A

CD18+, CD204+

Iba-1+

37
Q

What are common labwork abnormalities with HS?

A

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

38
Q

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

A

pancytopenia

39
Q

Histiocytic sarcoma

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

A
40
Q

What lung lobe is affected in HS?

A

R middle

41
Q

What is MST of periarticular form in comparison to toher forms?

Dogs with no evidence of metastasis at diagnosis?

A

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)

42
Q

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

A
43
Q

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

A
44
Q

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

A
45
Q

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

A
46
Q

Hemophagocytic HS originates in the what cells?

A

Mac, not the DC

47
Q

Hemophagocytic histiocytic sarcoma involves what organs?

A

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

48
Q

What are the common labwork abnormalities with hemophagocytic HS?

A

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

49
Q

Hemophagocytic HS is positive for what marker?

A

Confirmatory dx with histopath / stains – (CD11d+)

50
Q

Prognosis for dogs with HHS?

A

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

51
Q

Cats with histiocytic disease have what type of disease?

A

Multifocal or disseminated disease

52
Q

3 common findings in cats with histiocytic sarcoma?

A

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

53
Q

Treatment for cats with histiocytic sarcoma?

A

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

54
Q

Feline progressive histiocytosis where does it originate?

A

Originates in skin DCs and progresses to other organs

55
Q

How does feline progressive histiocytosis appear in cats?

A

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

56
Q

What is the clinical course for feline progressive histiocytosis?

A

Usually progressive over months or years (median 13.4 months)

57
Q

Feline PH spreads to what areas?

A

Spreads to LN, lungs, abdominal viscera

58
Q

Feline progressive histiocytosis

Gender predilection?

Treatment?

A

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

59
Q

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

A
60
Q

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

A

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