Histiocytic disease Flashcards by Bushra Zaidi

Tsai et al. Imaging characteristics of intrathoracic histiocytic sarcoma in dogs

Reviewed studies from 39 dogs

Most common findings noted by 1st and 2nd observer?

Common location in the lung?

Common LNs affected?

Intrathoracic lymphadenopathy - 82% and 87% and Pulmonay mass - 74% and 82%

Ventral aspect of the R middle

Sternal and tracheobronchial more common than cranial mediastinal

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Nielsen et al. Investigation of a screening programme and the possible identification of biomarkers for early disseminated histiocytic sarcoma in Bernese Mountain dogs

Construct a screening programe for DHS in Bernese Mountain Dogs

How were dogs identified?

What showed potential as blood borne marker?

MST for early DHS?

Screening program how often and diagnostics?

Diagnostic imaging (n=4)

Serum ferritin (n=1)

226 days (7.5 mo)

Every 6 months for dogs over 4 years including diagnostic imaging and ferritin

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Moore et al. 2012. Histologic and Immunohistochemical Review of Splenic Fibrohistiocytic Nodules in Dogs

Composed of malignant and non-malignant disease (SFHN)

32 dogs with SFHN

Median OS?

What was associated with survival time?

What diseases were SHFN reclassified?

Survival for dogs with HS?

387 days (~1yr)

Grade 3 SFHN

Nodular hyperplasia, lymphoma, stromal sarcomas and histiocytic sarcomas

74 days

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Kato et al. The Class A Macrophage Scavenger Receptor CD204 is a useful IHC marker of Canine Histiocytic Sarcoma

All the HSs expressed what markers?

Less commonly expressed markers for HS?

Round cell tumor expression for CD204?

CD204, CD18, MHCII

CD163 (27/50) and CD11d (7)

Negative except for 1 grade III MCT

CD204 is a useful marker for canine HS

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Barger et al. 2012. Cytologic identification of erythrophagocytic neoplasms in dogs

Identify neoplasms that exhibit erythrophagia

What were the neoplasms that exhibited erythrophagia?

Differentials for erythrophagia?

HSA (12/34), HHS (11), OSA (9), MCT (1), T-cell LSA (1)

Spindle cell sarcoma, OSA, HSA, HHS

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Ito et al. 2013. Identification of dasatinib as in vitro potent growth inhibitor of canine HS cells

Dasatinib targets several kinases

Examined effect in 6 HS cell clines and MDCK cells

Result?

Inhibited growth in 4 HS cell lines

Kinase targeted by dasatinib is crucial for growth in some HS

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Boerkamp et al. 2013. Gene expression profiling of histiocytic sarcoma in canine model: the predisposed FCR dog

Which genes were upregulated?

Which genes were downregulated?

Analysis revealed 24 pathways were involved in development of HS, most of which involved?

GTSF1, Col3a1, CD90, LUM

PPBP, SpiC, VCAM1, ENPEP, ITGAD

DNA repair and replication

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Kuijk et al. 2013. Periarticular Histiocytic sarcoma and previous joint disease in Bernese Mountain Dogs

PAHS may be more frquent around diseased joints in BMD

A significant association between joint disease and PAHS was demonstrated for which joints?

Left elbow, right elbow, right shoulder, left and right stifle, and left carpal joint

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Abbondati et al. 2013. An immunohistochemical study of expression of the hypoxia markers Glut-1 and Ca-IC in canine sarcomas

HIF-1 induces trasncription of Glut-1 and Ca-IC- endogenous markers of chronic hypoxia in humans

What was the expression of Glut-1 in HS?

What was positively associated with immunoreactivity score?

High compared to low grade STS

Intratumoral microvessel density

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Nielsen et al. 2013. Monocyte chemotactic protein-1 and other inflammatory parameters in BMD with disseminated HS

EValuate the immunological state of untreated BMD with DHS

Significant differences were not between BMD and healthy controls with which factors?

Fibrinogen, CRP, MCP-1 (monocyte chemotactic protein)

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Heinrich et al. 2014. Passage-dependent morpholocial and phenotypical changes of a canine histiocytic sarcoma cell line

Early passaged cells were characterized by round cell bodies with small cytoplasmic projections and later passages exhibited spindle shaped morphology with larger processes

The % of CD11c- CD14-, CD18-, CD45-, and CD80 positive cells were decreased in late passages

Expression of CD44, CD86, MHC I, MHC II and ICAm-1 remained unchanged

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Erich et al. 2013. Causes of death and the impact of HS on the lide expentancy of the Dutch population of Bernese mountain dogs and FCR

What % of deaths in BMD and FCR is associated with malignant tumors?

How many die from HS?

55% BMD and 64% FCR

1/7 (14%)

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Yamazaki et al. 2013. Inhibition of survivin influences the biological activities of canine HS cell lines

Survivin is an apoptotic inhibitor factor

Survivin gene levels in 30 HS specimens?

After transfection with survivin siRNA what happened?

Significantly high

Apoptosis, growth cell inhibition, enhanced chemosensitivity, and weaked phagocytic activities

No effect was seen in normal fibroblasts

Survivin may mediate aggressive biological activites of HS and may be a therapeutic target

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Yamazaki et al. 2014. Comparative analysis of mRNA expression of surface antigens between histiocytic and nonhistiocytic sarcoma in dogs

Surface antigens (SA) assesed CD11b, CD11c, MHC class IIa, CD86

SA mRNA expression in HS dogs to non-HS dogs?

Accuracy of the cutoff values were MHC Class IIa 88%, CD11b 86%, CD11c 86%, CD86 85%

Significantly higher in HS dogs

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Boerkamp et al. 2014. The two main forms of histiocytic sarcoma in predisposed FCR dogs display variation in gene expression

Microarray analysis of either soft tissue- or visceral HS

Which gene was upregulated in the visceral compared to soft tissue form?

Downregulated compared to soft tissue form?

CLEC12A and CCL5

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Kato et al. Immunohistochemical detection of the class A macrophage scavenger receptor 2014 using air-dried cytologic smears of canine HS

Validate an anti-human CD204 Ab

10 dogs with CHS and 45 dogs with other tumors

Results?

All 10 CHS showed intense positive staining in >50% cells the other 45 tumors were negative

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Pierezan et al. 2014. Immunohistochemial expression of ionized calcium binding adapter molecule 1 in cutaneous histiocytic proliferative, noeplastic and inflammatory disorders of dogs and cats

Iba1 is marker of glial cells and pan-macrophage marker

Which had strong cytoplasmic expression for Iba1?

Which were negative?

Cutaneous histiocytoma, reactive histiocytosis, HS, feline progressive histiocytosis, macrophage in cutaneous mycobacteriosis.

Melanoma, LSA, MCT, plasmacytomas

Iba1 does not differentiate between macrophage and dendritic antigen presenting cells or histiocytic disorders

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Yamazaki et al. 2015. Survivin suppressor (YM155) enhances chemotherapeutic efficacy against canine histiocytic sarcoma in murine transplantation models

HS cells with CCNU resistance, YM155 treatment did what?

Suppressed cell growth and cell resistance to CCNU

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Yamazaki et al. 2015. Influence of a survivin suppressor YM155 on the chemoresistance of HS cells

Elevated survivin expression in HS dogs corresponded with?

YM155 treatment?

Reduced DFI anf survival time and increased chemoresistance

Supressed cell growth and resistance to CCNU by inhibiting activity of ATP-binding cassette transporters

Cannon et al. Evaluation of a combination chemotherapy protocol including lomustine and doxorubicin in canine HS

CCNU and DOX alternating every 2 weeks

15/17 dogs had disseminated disease

Side effects?

Overall response rate?

Median time to progression?

Overall MST?

Dose reductions in 18% of cycles

58%

185 days

Hostettler et al. Post mortem CT and core needle biopsy in comparison to autopsy in eleven BMD with HS

Thongthard et al. 2016. Histological and immunohistochemical studies on primary intracranial canine histiocytic sarcomas

Where were the tumors mainly located?

Predominant clinical sign?

Significant association noted between?

Tumor cells were stongly positive for what IHC markers?

Ki67 proliferative index?

Cerebrum, particularly frontal lobe

Seizures

Tumor cell type and hemophagocytic activity

HLA-DR, Iba-1, CD204 (23 cases), INOS (20), CD163 (17), CD208 (9), Lysozyme (8), S100 (5)

0.5-64%

Primary intracranial HS exhibit both dendritic and macrophage phenotye

Borresen et el. 2017. Circulating let-7g is down-regulated in BMD with disseminated histiocytic sarcoma and carcinomas - a prospective study

miRNA let-7g was downregulated in dogs with cancer and dogs with DHS compared to healthy controls

Known tumor suppressor gene

Tagawa et al. 2016. Evaluation of Costimulatory Molecules in Peripheral Blood Lymphocytes of Canine Patients with HS

Dogs with HS, other tumors, and healthy controls

CTLA-4 expression on CD4+?

CTLA-4 expression on CD8+?

PD-1 expression on CD8+?

IFN-g and CD28 expression?

Significantly higher in HS group than in control group

No difference

***Ishikawa et al. 2016.* Comparison of conventional MRI and nonenhanced 3D time of flight MR angiography findgins between dogs with meningioma and dogs with intracranial HS: 19 cases** 14 dogs with meningioma and 5 with IHS Tumor type was significantly associated with signal intensity on? Tumor type was not associated with? Vessel adjacent to meningiomas were displaced in 8/9 dogs and with IHS not displaced

T2-weighted and fluid-attenuated inversion - meningiomas were hyperintense and most IHS were isointense or hypointense Signal uniformity, tumor location, tumor orignin, edema, midline shift, brain herniation

***Ruple et el. 2016.* Risk factors associated with development of HS in BMD** Dogs diagnosed with ____ condition were found to be more likely to develop HS? Dogs receiving prescrition ____ were found to be considerable lower risk?

Orthopedic conditions Anti-inflammatory medications **Inflammation may be modifiable risk factor for the development of HS**

***Dervisis et el. 2017.* Clincial prognostic factors in canine histiocytic sarcoma** Most comonly represented breed? Median survival for all dogs? Negative factors associated with survival?

BMD (53), Labrador retriever (26) and Golden Retreiver (17) 170 days Palliative treatment, disseminated HS, use of corticosteroids

***Faller et al. 2016.* Retropsective characterisation of solitary cutaneous histiocytoma with LN metastasis in 8 dogs** Samples were positive for and negative for? E-cadherin? Outcome known for 3 dogs?

CD18 postive and CD11d negative Reactivity varied 1682 days, 570 days, 318 post-diagnosis (1-4 years) **Metastatic histiocytoma is rare but some may have favourable outcome**

***Moore et al. 2017.* Chemotherapy for dogs with LN metastasis from HS** 12 dgos with HS metastatic to LN treated with surgery with and without chemotherapy MST for 8 dogs that received chemotherapy? 1- and 2- year estimated survival? MST for 4 dogs with LN mets and no chemo?

219 days (7.3 mo), 38% 57 days none alive at 1 year

***Marcinowska et al. 2017.* T lymphocytes in Histiocytic Sarcomas of Flat-Coated Retriever Dogs** 40 tumors to examinat T regulatory cells Foxp3 expression? FOXP3 versus CD45RA Difference in expression may be related to?

95% of infiltrating T cells were positive by IHC cell positive for FOXP3 were higher in soft tissues, CD45RA positive cells was higher in splenic origin HS Differences in the tumor microenvironment

***Thongthard et al. 2017.* Variations in Histiocytic Differentiation of Cell Lines From Canine Cerebral and Articular Histiocytic Sarcomas** 2 new cell lines - PWC-HS01 and FCR-HS02 obtained from brain and articular tumors PWC-HS01 expressed dendritic (S100, CD208, CD1, CD4) and macrophage (CD68, CD163, CD204 markers) FCR-HS02 negatve for CD204 and CD68 and positive for dendritic cell markers HS from CNS may have tendency to more undifferentiated compared from other organs

Wada et al. 2017. Comparisons among MRI signs, apparent diffusion coefficient, and fractional anisotropy in dogs with solitary intracranial meningioma or HS

***Kezer et al. 2017.* Efficacy of dacarbazine as a rescue agent for HS in dogs** 17 dogs with disseminated disease prior tx with CCNU Overall response rate? Median event free survival? Median EFS for dogs that experienced objective response?

18% with 3 PR 21 days 70 days

***Lenz et al. 2017.* Histiocytic sarcoma in 14 minature schnauzers - a new predisposition?** 14 MS with HS 10 had localized disease and 4 had disseminated disease 9 had primary pulmonary HS (7) without intrathorathoracic metastasis (2), 1 had gatric HS with nodal metastasis Pedigree analysis revealed common ancestor - **inherited risk factor**

***Mason et al. 2017* Epirubicin in the treatment of canine HS: sequential, alternating and rescue chemotherapy** 29 dogs alternating epirubin and lomustine - ORR? BRR? Median time to progression? MST? Dogs treated in resceue setting with epirubin - ORR? BRR? Median TTP?

29%, 71%, 69 days, 185 days 19%, 63%, 62 days

***Manor et al. 2017.* Prior joint disease is associated with increased eisk of periarticular HS in dogs** Study included variety of dog breeds Dogs with PAHS were more likely to have ____ in the tumor affected joint compared with control population? A total of \_\_\_% with stifle PAHS had prior joint disease

Joint disease 88% Association with joint disease and PAHS also applies to other breeds

Thaiwong et al. 2017. Gain of function mutation in PTPN11 in HS of BMD

***Nakano et al. 2017.* Flourescein sodium-gated resection of intracranial lesions in 22 dogs** **Adverse effect was vomiting in 2 dgos** Pattern between preoperative Gd enhancement and intraoperative FS? High grade glioma and HS had more ____ FS staining Lesions with strong Gd enhancement, meningiomas and choroid plexus tumors, also had ___ FS staining

Agreed Intense Intense

***Pinto da Cunha et al. 2014.* Cytologic and Immunohistochemical characterization of feline progressive histiocytosis** Neoplatic cells expressed? E-cadherin expression? Absent birbeck granules in 1 case

CD1a, CD1c, CD11b, CD18, MHC II Positive except for 1

***Treggiari et al.* Clinical outcome, PDGFRB and KIT expression in feline histiocytic disorders: a muticenter study** 5 FPH, 8 HS, 2 HemoHS PGFRB and KIT expression? PR noted with TKI and CCNU, and RT Survival time shortest with?

Variably positive in most and KIT negative in all HemoHS **PDGFRB may represent therapeutic target but not KIT**

***Fayyad et al. 2018.* Matric metalloproteinases expression in spontaneous canine HS and its xenograft models**

***Marlowe et al. 2018.* Primary pulmonary HS in dogs: a retropsective analysis of 37 cases** 37 dogs: 13 CCNU alone, 18 Sx and CCNU, 3 medical management, 3 surgery alone Median PFS and OS? Measurable responses noted in dogs receicinv? Which group had prolonged survival? What negatviely impacted PFS?

197 (6.6 mo) and 237 days (8 mo) chemotherapy - not durable with PFS 91 days and OV 131 days Surgery and chemotherapy - PFS 276 days (9.2 mo) Clincial signs or metastasis at time of diagnosis

***Toyoda et al. 2019.* Clinicopathological characteristics of HS affecting the CNS in dogs** 100 dogs with HS and 62 with meningiomas Predisposition of CNS HS in what breeds? Corgis and Shetlands had what type? Rotties? Primary was characterized by? What was noted in all dogs relative to controls? WHat resulted in improved survival time?

BMD, Goldens, Rottie, Corgis, Shetland Sheepdogs Primary tumors. Disseminated. Marked CSF inflammation and neoplastic cells noted 52% in CSF Increased neutrophil to lymphocyte ratio Definitive versus palliative treatment

***Quinci et al. 2019.* Ultrasonographic Honeycomb pattern of the spleen in Cats: Correlation with Pathological Diagnosis in 33 Cases** 33 cats - 15 lymphoid hyperplasia, 8 LSA (4 B and 3 T and 1 LG), 6 splenitis, 3 EMH, 1 HS Presence of LSA with HCP in spleen? Most common feature with HCP in cats LSA? Visualization with linear and micro-convex transducers?

24% Splenomegaly 100% and 62.5%

***Asada et al. 2019* Effect of two-base insertion mutation of the TP53 gene on expression of p53 protein in canine histiocytic sarcoma cells** Effect of common 2-base insertion mutation in exon 5 of TP53 gene Expression of p53 protein and its function as TF were lost after mutation in canine histiocytic tumor cells

***Igase et al. 2019.* Anti-tumor activity of oncolytic veovirus against canine histiocytic sarcoma cells** Reovirus can replicater and induce caspace-dependent apoptosis in canine HS cell lines A single intratumoral injection suppressed growth of SQ grafted tumors in NOD/SCID mice Cell death attributed to type I IFNA induced by reovirus