Sick - Johns Hopkins Medicine

Sick (& not so sick) Mice 

NON Infectious Phenotypes 

Cory Brayton, D.V.M., D.A.C.L.A.M., D.A.C.V.P. 

Associate Professor, Molecular and Comparative Pathobiology 

No 

Phenotype ? 

Really ? 

Brayton - NON infectious - P 1 

Some Phenotypes (& Pathology) of 

‘Normal’ mice (short list) 

C57BL/6? Microphthalmia, hydrocephalus, ulcerative 

dermatitis, osteoporosis, presbyacusis, AMP, amyloidosis, 

lymphoma, histiocytic sarcoma .… 

129? Teratomas (Ter), lung tumors, AMP, hyalinosis, 

acallosity, megaesophagus, otitis, lymphoma … 

FVB? rd1, seizures, lung tumors, AMP, mammary/ pituitary 

dz …. 

Director, Phenotyping Core 

Johns Hopkins University, School of Medicine 

Baltimore, MD 21205 

phenocore@jhmi.edu 

http://www.hopkinsmedicine.org/mcp/PHENOCORE/index.html 

DEAF‐ C57BL/6, BALB, DBA, etc 

BLIND dt rd1 ‐ C3H, CBA, SJL, SWR, FVB 

C5 deficient 

4 

5 

AIMS 

1. Select the best mice for YOUR aims 

2. Expect the Expected 

– Recognize unexpected phenotypes 

3. Strategic Pathology to diagnose 

problems and unexpected findings 

Improve model selection, experimental 

design, data analysis and reporting to 

achieve robust, relevant, reproducible, and 

’t l t bl ’ h 

6 

Important? 

‘PHENOTYPES’ 

Size ‘developmental delay’ 

Pup death 

Behaviors 

Immunity 

Fertility 

Lifespan 

Respiratory disease 

Wasting ‘premature aging’ 

Mortality 

Cancer 

Important ? 

Some Non‐ infectious 

Phenotypes to expect 

Malocclusion 

Hydrocephalus 

Sexual dimorphisms 

Blind / Deaf 

SKIN/HAIR: Barbering / dermatitis 

Imperforate vagina 

MUS Hydronephrosis 

Vestibular syndromes 

Acidophilic Macrophage pneumonia 

Amyloidosis & glomerulonephritis 

Arteritis 

Tumors 7 

Other ‘PHENOTYPES’ 

affected 

Size ‘developmental delay’ 

Pup death 

Behaviors 

Immunity 

Fertility 

Lifespan 

Respiratory disease 

Wasting ‘premature aging’ 

Mortality 

Cancer 

X 

Important? 

Malocclusion 

Hydrocephalus 


Blind / Deaf 

SKIN/HAIR: Barbering / dermatitis 




Acidophilic Macrophage pneumonia 

Amyloidosis & glomerulonephritis 

Arteritis 

Tumors 

8 

cbrayton@jhmi.edu 2013 

Especially with small n, 

any of these conditions in 

control or experimental 

groups could impact 

significance …. 

Can they interfere with 

your study ? 

Can you diagnose them ? 

X 

Expected Phenotypes 

IF you look… 

Malocclusion 

Hydrocephalus 


Blind / deaf 

SKIN: Barbering / dermatitis 




SICK OLD MICE dt: 

• Acidophilic Macrophage Pneumonia 

• Amyloidosis & Glomerulonephritis 

• Arteritis 

• Tumors 

9 

Younger mice 

(By weaning) 

Various ages 

Older mice 

Discussion Plan 

Important Phenotypes 

1. Sexual dimorphisms 

2. 2 killers to identify at/by weaning 

3. 3 Common clinical complaints 

4. 4 Sick old mouse phenotypes 

5. Top 5 tumors 

AIM: DON’T LET THESE MESS UP YOUR RESEARCH 

10

X 

1. Some Sexual Dimorphisms 

Size growth curves = NICE DATA ! 

• Are the GEM really smaller? Slower growing ? 

Anogenital distance –tough in younger 

• In utero influences 

Nipples –not in males 

Salivary glands – bigger in males 

• Acidophilic tubules 

Kidneys – bigger in females ? Males ? 

• Cuboidal parietal epithelium –male (>> female) 

Adrenal glands – bigger in females 

• X zone (vacuolar change in females) 

11 

1. Some Sexual Dimorphisms 

If they’re normal, 

what’s the big deal? 

Are there sexual dimorphisms in your data, or 

research endpoints ? 

ANALYZE Male & Female data separately 

ALSO CONSIDER: NOT having these may be an 

important phenotype 

12 


Sex and SIZE 

(+ Genetic Background) 

SIZE (body weight) 

M > F 

B6D2F1 ~ Hi? 

C3H/HeJ ~ lo 

Jax Phenome Database for 

physiological data by strain sex 

age protocol 

– Jax Pheno1 

– n = 5‐15 

– 6% fat diet NIH 316 Purina 5K52 

13 

♂ 

♀ 

Sexual Dimorphisms 

Which is Male? A or B ? 

Check 

Anogenital distance 

Nipples 

♀ ♂ 

A B 

Sexing pups 

Nice pictures at 

http://www.thefunmouse.com/info/sexing.cfm 

Salivary Glands, associated Nodes 

Which is Male ? 

A 

A or B ? 

1. Submandibular 

2. Sublingual B 

3. Parotid 

(exorbital lacrimal) 

4. Lymph nodes 

14 

Nipples may be evident by about 6do 16 

A 

Tissues? 

Which is Male? 

B 

Tissue? 

Which is more likely to be male? 

A 

B 

A 

FEMALE 

Tissue? 

Which is Female ? 

B 

cbrayton@jhmi.edu 2013 17 

18 

19

X 

1. Sexual Dimorphisms 

Size Growth Curves = NICE DATA ! 

Salivary glands, Kidneys, Adrenal glands etc 

Many More 

CONCLUSIONS: 

EXPECT THE EXPECTED –consider the unexpected 

ANALYZE Male & Female data separately 

Missing Dimorphisms may be a phenotype 

20 

X 

2. 2 Young Mouse Phenotypes 

to identify by / at weaning: 

1. Hydrocephalus 

• Later onset not evident at weaning 

E.g. sporadic in MRL etc. 

2. Malocclusion / Incisor overgrowth 

• Cull or trim 

• Breed?? 

3. Microphthalmia 

• Expect this in C57BL – but it won’t kill them 

• Especially? Right eye in females 

21 

22 

Hydrocephalus 

Especially C57BL 


Malocclusion Phenotypes 

6g –6 weeks old 

Developmental delay’ 

Early Death 

23 

X 

2. 2 Young Mouse Phenotypes 

to identify by / at weaning: 

1. Hydrocephalus 

2. Malocclusion / Incisor overgrowth 

3. Microphthalmia etc 

CONCLUSIONS: 


DON’T let these kill your mice ! 

Examine your mice 

– weaning is a good time to weigh them too 

24 

X 

3. 3 Common 

Clinical Complaints 

1) Skin Disease 

1) Barbering –more common 

2) Ulcerative Dermatitis –more serious 

3) Flakey skin ‐ in immunodeficient – discussed later 

4) Tumors – discussed later 

5) Mites – discussed frequently 

2) Abdominal distention 

1) Pregnancy 

2) Hydrometra mucometra pyometra 

3) Hydronephrosis (MUS) 

4) Neoplasia – effusion, organomegaly 

5) Effusion ‐ Neoplasia ? Heart or kidney disease? 

253) Neurologic signs 

1 st Clinical Complaint: Skin 


26 

Alopecia 

– Social phenomenon F > M 

– Vibrissae are important in 

some behavior tests … 

Skin Alopecia 

Barbering 

– Strain/sex specific 

patterns 

– Nibbled 

• Not plucked – 

ouch! 

– Vibrissae are 

important in 

some behavior 

tests … 

Kalueff 27 et al. 2006. 

129S1 ♂ NMRI ♂ C57Bl/6 ♂ 

C57Bl/6 ♀ NMRI ♀ A/J ♂ 

♂ 

X 

SKIN: ulcerative dermatitis 

Mouse Ulcerative 

Dermatitis (MUD) 

• Interferes with a lot of research 

• Secondary phenotypes: 

Leukocytosis 

Lymphadenomegaly, 

Splenomegaly 

Amyloidosis, 

GN 

Sick mice 

Mortality 

C57BL > others 

28

2 nd Clinical Complaint 

Abdominal distention 

‘Pregnant x weeks… months ’ 

Don’t ignore – NOT likely to have pups…. 

Mouse gestation ~ 19‐21 d….. 

29 

30 

Hydronephrosis 

Probably / Usually Urinary obstruction 

– Has been called mouse urologic syndrome (MUS) 

Role of Genetic Background ?? Diet ?? Caging ?? 

Polycystic kidneys are polycystic – 

– Multiple cysts, genetic 

Hydrometra, mucometra 

Progressive abdominal distention – weeks … 

– Imperforate vagina 

– Vaginal septa 

– Esp BALB/c, B6? 

– Note perineal bulge 

– Usually infertile 

– Pyometra – 

discussed later 

31 


X 

3 rd Clinical Complaint 

‘Neurologic’ 

1. Paralysis, posterior paresis 

a) Neoplasia ‐ – discussed later 

b) Infectious demyelination –MHV, TMEV – discussed later 

c) Autoimmune demyelination – Induced –EAE etc 

d) Trauma, induced, muscular dystrophy? other 

2. Spinning, Rolling ‐ Dizzy, Vestibular 

a) Otitis –infectious– discussed later 

b) Arteritis – discussed later 

c) Infarct ~ stroke ? 

d) Trauma, induced, other 

3. Seizures (sudden death) 

a) FVB/N, DBA/2 other genetically susceptible 

32 

b) Other ‐ Induced? Chemical ? Genetic ? 

33 

'Neurologic‘ #1: Posterior Paresis 

Important phenotype? 

1. Neoplasia 

2. Infectious demyelination 

• MHV, TMEV, LDV 

3. Autoimmune demyelination 

• Induced –EAEetc 

4. Other Induced/experimental? 

• Iatrogenic? Trauma? 

• Muscular dystrophy? 

• other ? 

'Neurologic' #2: Rolling, 

Spinning, Head tilt (vestibular) 

Dizzy mice –GEM Model 

of vestibular syndrome? 

Consider: 

34 

1. Otitis? 

2. Arteritis ? 

3. Tumors? 

4. Other? 

Dumb mice? 

or Dizzy ? 

Vestibular Signs 

Rolling, turning 

Head Tilt 

Malacia, necrosis compatible 

with ischemia/infarct 

Southard & al 2007, 

2010 

Acute onset spinning 

(vestibular signs) 

death 

>12 mice of 2 Swiss 

stocks; 

1 source –local 

'Neurologic' #3: Seizures 

Important phenotype? 

In what strains do you expect seizures ?? 

• FVB/N 

• DBA/2 

Consider 

• Tumors 

• Induced ‐ Kainic acid etc, surgical, IC inoculation 


35 36 

37

X 

38 

1. Skin Disease 

3. 3 Common 

Clinical Complaints 

2. Abdominal distention 

3. Neurologic signs 

CONCLUSIONS: 


Examine your mice – 

Consider pathology to assess further 

Don’t let these mess up your research. 

X 

4. 4 Sick Old Mouse 

Phenotypes 

1. Amyloidosis – multisystem 

– Rule out glomerulonephritis 

2. Arteritis – multisystem 

3. Hyalinosis & Acidophilic macrophage pneumonia 

4. Neoplasia 

39 

– Sporadic – common on different genetic backgrounds 

– Histopathology to diagnose 

– MANY other conditions – but not so likely to contribute to 

morbidity mortality, e.g. : 

• Angiectasis, melanosis, mild mineralization, inflammatory infiltrates, 

pancreatic … 


Phenotype: wasting, 'premature aging' 

Amyloidosis, intestine 

Intestine (ileum) first & worst 

• Usually earlier & more severe than kidney, etc 

40 

Amyloidosis, kidney 

(pink stuff in glomeruli) 

Glomerulonephritis can be common & 

resemble glomerular amyloid 

(pink stuff in glomeruli) 

Amyloid is Congo Red POSITIVE / PAS negative 

GN usually is Congo Red negative / PAS POSITIVE 

H&E 

PAS 

41 42 

Mouse Amyloidosis 

Phenotypes 

Gut – Intestinal amyloid 

malabsorption 

Kidney – Glomerular amyloid protein loss 

Liver – Hepatic amyloid 

• Adrenal 

• Salivary glands 

• Tongue 

• Heart 

• Stomach 

• Testes 

43 

size, function 

Weight loss & Wasting 

‘Premature Aging’ phenotype 

e.g. in SAMP Senescence 

Accelerated Mice 

Mouse Amyloid 

2 types 

WERE COMMON complicators of chronic studies 

– less ‘clean’ conditions 

1. Reactive, Secondary, AA – SAA 

• SAA serum amyloid A component 

Acute phase response protein 

• chronic immune stimulation –GI, kidney, spleen 

2. Senile, ASSAM amyloid – Apoa2c >> Apoa2a 

44 

• Apolipoprotein A2 (part of HDL ) 

• Alleles a,b,c,d,e 


allele 

ApoA2 a 

ApoA2 b 

ApoA2 c 

ApoA2 d 

ApoA2 e 

45 

Strains 

Apoa2 gene/locus 

AKR, BTBR, C57BL/6J, C57BL/1, DBA/2 

SAM‐P3, SAM‐P8, SAM‐R2 

129S1, BALB/CJ, BALB/cByJ, C3H/, CBA, FVB/NJ, MRL, NZW etc 

SAM‐P6, SAM‐R1 

A/J, SJL/J etc 

SAM‐P1, SAM‐P2, SAM‐P7, SAM‐P9, 

PERA, WSB 

SPRET 

c allele EARLY ASSAM onset in liver spleen 

• ‘aging phenotype’ 

a allele ‐ later onset in gut, lung, tongue etc. 

b allele –QTL associated with higher HDL level 

• Summarized from Higuchi & al 1991; Wang & al 2004 

Arteritis, periarteritis 

Often incidental, not associated with 

clinical signs, in chronic studies on 

various strains 

Also implicated in Vestibular 

syndrome, or death (with severe 

cardiac involvement) 

46 

Heart 

Head

Pretty histology 

Acidophilic Macrophage 

Crystalline ‘Pneumonia’ 

47 

Acidophilic Macrophage or 

Acidophilic Crystalline ‘Pneumonia’ 

Spectrum of clinical Phenotypes 

No clinical disease TO Respiratory distress, death 

Spectrum of Anatomic Pathology Phenotypes 

Scattered Acidophilic 

Macrophages or 

Crystals 

TO 

Pulmonary consolidation by 

acidophilic macrophages & 

crystals 

Associations with Pneumocystis etc. agents? 

– In immunocompromised / immunoweird mice 

especially? On B6 or 129 background ? 


YM1, YM2 chitinases in Hyalinosis & 

Acidophilic Macrophage Pneumonia 

Haines et al. 2001. Toxicol Pathol. 29(6):653‐61. Pathology of aging B6;129 mice. 

– Hyalinosis with extracellular crystals multiple sites (respiratory, gall bladder, 

stomach) 

Ward et al. 2001. Hyalinosis and Ym1/Ym2 gene expression in the stomach and respiratory 

tract of 129S4/SvJae and wild‐type and CYP1A2‐null B6, 129 mice. AJP 

– Hyalinosis (eosinophilic cytoplasmic change) in glandular stomach, respiratory tract, bile duct, 

and gall bladder of B6,129 CYP1A2‐null & wild‐type mice 

– Also in both sexes of background 129S4/SvJae strain (WT) 

– Ym1 in normal and abnormal NOSE olfactory + respiratory, lung, marrow, stomach 

– Ym2 in hyaline Stomach lesions 

Nio et al. 2004. Histochem Cell Biol.121(6):473‐82. Cellular expression of murine Ym1 and Ym2, 

chitinase family proteins, as revealed by in situ hybridization and immunohistochemistry. 

– chitinase family proteins, widely distributed, bind GAG’s such as heparin/heparan sulfate. 

– Ym1 is a macrophage protein produced in parasitic infections… 

• Lung ‐‐ Ym1‐expressing cells are alveolar macrophages, Ym1 localized in RER. 

 

• Spleen ‐‐Ym1‐expressing cells in the red pulp identified as immature neutrophils. 

• Marrow ‐‐ immature neutrophils immunoreactive lose immunoreactivity with maturation. 

• Marrow ‐‐ needle‐shaped crystals in macrophages showed intense Ym1 immunoreactivity. 

48 – Ym2 expression restricted to gastric squamous 49 epithelium in junctional region 

Hyalinosis in other tissues 

Pretty histo – nose, stomach, gall bladder 

Crystals in marrow spleen – macrophages, PMN 

Thoolen, B., R. R. Maronpot, et al. (2010). "Proliferative and Nonproliferative Lesions 

of the Rat and Mouse Hepatobiliary System. Tox Path. 2010;38:5S 

INHAND Nomenclature 

Fig 25. Rat liver. Pigment in hypertrophic 

hepatocytes consistent with bile. 

Cholestasis. 

Fig 26. Mouse liver. Hyalinosis of 

hyperplastic bile ducts with crystal 

formation and peribiliary inflammatory 

cell infiltrate. 



formation and peribiliary inflammatory 

cell infiltrate. Higher magnification of 

Figure 26. 



formation. 

Fig 29. Mouse liver. Numerous 

intracytoplasmic hyaline bodies in an 

hepatocellular adenoma. 

Fig 30. Mouse liver. Intranuclear inclusion 

51 body, cytoplasmic invagination. 

50 Copyright © by Society of Toxicologic Pathology 

X 

4.4 Sick Old Mouse 

Phenotypes 

1. Amyloidosis – multisystem 

– Rule out glomerulonephritis 

2. Arteritis – multisystem 

3. Hyalinosis & Acidophilic macrophage pneumonia 

4. Neoplasia – discussed Next 

CONCLUSIONS 

EXPECT THE EXPECTED –consider the UNexpected 

PATHOLOGY to diagnose 

Don’t let the expected conditions mess up your research 

52 

X 

Mouse Cancer Quiz 

1. Thymic Lymphoma 

2. B cell Lymphoma 

3. Plasma cell tumors (myeloma) 

(Harderian, myoepithelioma, 

Rhabdomyosarcoma etc ) 

4. Lung tumors 

5. Mammary tumors 

6. Mammary Hyperplasia, 

EMT with pituitary tumors 

7. Liver tumors 

8. Cancer resistant 

a) A 

b) AKR, NODscid, C58 

c) BALB/c 

d) C3H 

e) C57BL/6 

f) FVB/N 

g) SJL/J 

WHAT SHOULD YOU EXPECT IN YOUR MICE ? 

53 


X 

54 

5. 5 Mouse Tumors 

Tumor Sex Strain predisposition 

Hematopoietic 

Lymphoma, HS 

Lung 

F>M 

AKR, SJL/J, NODscid 

(C57BL, etc) 

A (FVB, 129, etc) 

Mammary F>>M C3H (BALB etc) 

Liver M>>F C3H, CBA, (B6C3 …) 

Pituitary 

F > M 

What strains are famous for what tumor? 

• Good or Bad for your model ? 

Is your favorite strain tumor resistant? 

Rodent Cancer Classification 

MMHCC – http://emice.nci.nih.gov/ 

– mouse models of human cancer consortium 

• Consensus papers hematopoietic liver mammary 

prostate intestine …. 

• GEM oriented 

INHAND http://www.toxpath.org/nomen/ 

– International Harmonization of Nomenclature 

and Diagnostic Criteria in Toxicologic Pathology 

• Rat is complete, mouse is coming 

• Tox oriented e.g. FDA GLP studies 

55

56 

Lymphomas 

Hematopoietic Tumors 

Mouse V Human 

– Thymic L (younger) 

– Follicular B cell 

Histiocytic sarcoma 

Leukemias 

– ALL in children 

– AML in adult 

Lymphomas 

Retroviruses as genetic – Diffuse large B cell 

engineers 

FCC lymphomas 

Common features 

• Point mutations 

• Activated Oncogenes 

• Inactivated Tumor suppressors 

Mouse Hematopoietic Tumors 

Spontaneous 

Distribution T‐cell lymphoma B‐cell lymphoma Histiocytic sarcoma Myeloid leukemia 

Systemic 

(generalized) 

Common Rare Rare Rare 

Thymus Primarily Rare Rare Rare 

Spleen 

Rare 

Common–follicular 

or marginal zone 

Occasionally –red pulp 

origin 

Common 

Peyer's patches Rare Common Occasional Rare 

Mesenteric Lnodes Rare Common Occasional Rare 

Liver Rare Rare Common Rare 

Uterus Rare Rare Common Rare 

Peritoneum Rare Rare Common Rare 

Skin Rare Rare Occasional Rare 

Bone marrow Rare Rare Rare Occasional 

IHC CD3 CD45r (B220) Pax5 CD68, F480 

57 

X 

From Table 1 - Ward 2006 Lymphomas and leukemias in mice. 


Spontaneous #1 

Thymic lymphoma (T lymphoplastic 

Lymphoma) 

• B cell tumors are rare in thymus 

Early onset often < 1y 

• Thymus 1st disseminates 

• Short studies … in 

AKR, C58, scid, NODscid 

Kras activation 

Endogenous retroviruses 

58 




Clinical Signs: 

Gross Lesions: 

Histology 



Overall ‘blue 

– Starry sky ? 

Blue cells + 

tingible body 

macrophages’ 



Follicular B cell lymphoma 

– Not exactly FCC ‐ 

Most common tumor or lymphoma in some strains 

GALT, nodes, spleen etc 

Later onset often > 1y 

Expect it in control mice > 1yr 

Endogenous retroviruses 

59 

59 

60 

60 

61 



Clinical Findings: 

Gross Lesions: 



Lymph node 

• Blue tumor 

• Monotonous 

population of 

similar cells with 

not much 

cytoplasm 

– Lymphoma. 



Histiocytic Sarcoma 

Most common tumor in some strains 

Liver Uterus spleen nodes etc 

Later onset often > 1y 

Expect it in control mice > 1yr 

Not such a blue tumor … 

Not so round cells either … 

62 


2013 

• Leukemia ? 

63 

64 

Clker.com



Histiocytic Sarcoma 

– Organomegaly 

• Liver 

• Uterus 

• Invades anywhere 

– Pleomorphic ‐ 

sarcomatous 

– Not so blue 

– Erythrophagocytosis 

65 

• Can be prominent 



HS –not so blue 

– Very Pleomorphic here 

66 

– Very nasty too 

'Paralyzed mouse' 

CONSIDER: 

– Neoplasia 

• Lymphoma 

• Histiocytic sarcoma 

• Sarcoma, poorly differentiated or 

osteosarcoma, esp in Trp53 

mutant 

– Demyelination? 

• MHV, TMEV, induced 

–Trauma? Fracture etc 

PATHOLOGY 

67 


Paralyzed mouse 

X 


Spontaneous 

Mouse Lung Tumors 

Lymphoma. 

Not the desired 

Neurologic 

phenotype….. 

68 

Lymphomas & histiocytic sarcoma 

– Especially in old mice & susceptible strains 

Leukemias not so common BUT 

advanced lymphoma or histiocytic 

sarcoma likely to involve marrow, blood 

– Ulcerative dermatitis and nasty infections 

are more common/likely causes of elevated 

69 

WBC in mice. 

70 

Adenomas 

Small 

Discrete 

Compress 


Especially A strain mice 

Adenoma > Carcinoma 

Adenoma ‐ smaller 

– Patterns: Solid > papillary > 

mixed 

Carcinomas ‐ bigger 

– Papillary > mixed 

– May metastasize to liver 

Wang & al. 2006. 

Look like spontaneous but 

Nikitin, & al. (2004). 


Kras+/‐ &TRP53 TG 

71 

X 


Terminology 

MMHCC: “Lung, adenoma or carcinoma” 

• Withhold the term ‘Bronchioloalveolar’ 

INHAND/Tox: A/B is still used 

• ‘Alveolar/Bronchiolar’ – Descriptive, but may not be cell of 

origin … DO NOT confuse with: 

Human BAC = adenocarcinoma with pure 

bronchioloalveolar growth pattern, no stromal, 

vascular or pleural invasion. 

– Lepidic pattern ~ aerogenous 

dissemination or lepidic spread 

72 

Lung Tumors 

Mouse V Human 

Common in A >> 

• 129, FVB/N >> B6, DBA 

Peripheral 

• Bronchiolar v alveolar 

v clara cells 

Multiple –often 

Adenoma > Carcinoma 

Kras activation 

Trp53 inactivation 

73 

• Esp in carcinogen induced tumors 

Most common 

neoplasm? 

Most common CA death 

NSCLC (80–85%) 

– Adca increasing 

– Smoking carcinogens 

SCLC (15–20%) 

KRAS activation (30‐50%) 

TRP53 inactivation

X Mouse Mammary Tumors 

Spontaneous 

C3H > other strains 

– CBA developed as resistant control strain 

BALB/c, 129 etc 

FVB/N get hyperplasia, EMT 

How MMTV Bittner agent was discovered 

74 

– Transmitted in milk – cytoplasmic inclusions 

– Reduced incidence by fostering 

– Endogenous Mtv’s involved in later tumors too 

X 

Mouse Mammary Tumors 

Terminology 

‘Preneoplastic’ lesions 

• HAN Hyperplastic alveolar nodules 

• Plaques 

• MIN mammary intraepithelial nodules –GEM 

Adenoma 

Carcinoma 

Pattern descriptors 

Etiology descriptors 

75 

MOUSE Mammary Tumors 

Tumors 

Hyperplasia 

C3H, etc 

Pregnant? 

FVB/N –pituitary tt? 

MMTV 

76 


FVB/N 

Mammary hyperplasia ‘neoplasia? 

79 

Mouse Mammary Tumors 

V Human Breast Tumors 

SIMILARITIES 

Molecular lesions 

Some morphologies 

Consistent with multihit 

kinetics 

Metastatic in both 

Cf Thompson 81 and Cardiff 

DIFFERENCES 

Mouse MT met to lung. 

– Human met to regional L nodes 

Hu more ductal Ca 

Mouse MT have less fibrosis 

and inflammation 

Most mouse MT are hormone 

Independent 

– ~1/2 of human breast Ca are 

hormone‐dependent. 

MMTV’ & Mtv’s in Mice 

– H hepaticus increased MT 

in a mouse model 

Gross 

Mouse Liver Tumors 

– nodules: single to multifocal coalescing 

Histology 

82 

– Foci of cytoplasmic alteration 

• Eosinophilic + Clear cell > Basophilic or mixed 

– Adenomas more common than CA 

– Carcinomas may arise in adenomas 

– Hepatoblastomas may arise in Ca 


C3H, CBA > other strains; M>>F 

http://dir.niehs.nih.gov/dirlep/liver2/MLIVER/mmenu.htm 

Maronpot 


83 

X 


Foci of cellular alteration 

– Eosinophilic, basophilic, clear, mixed 

Hepatocellular Adenoma (Type A nodules /tumors) 

– Well demarcated, usually < 10mm 

Hepatocellular Carcinoma (Type B nodules/tumors) 

– Trabecular, adenoid > solid patterns 

– Well to poorly differentiated 

– Usually poorly demarcated, > 10mm 

Hepatoblastoma usually arise in/near carcinomas 

– GEM 

• http://dir.niehs.nih.gov/dirlep/liver2/MLIVER/mmenu.htm Maronpot 

• Thoolen, Maronpot, et al. (2010). "Proliferative and Nonproliferative 

Lesions of the Rat and Mouse Hepatobiliary System. Tox Path. 2010;38:5S 

84 INHAND Nomenclature 


C3H, CBA, B6C3F1 

M > F 

C3H up to 90% incidence in M @14m 

Hcs (Hepatocarcinogen sensitivity) loci 

Role of Helicobacter etc. Microbes? 

• A/J Liver tumors 

85

Spontaneous tumors to expect : 

SCC TCC MH 

Briard 

Standard poodle 

Gordon Setter 

Giant Schnauzer 

Profiling 

Not always a bad thing 

Scottie 

Westie 

http://research.nhgri.nih.gov/dog_genome/ 

86 

Bernese Mtn dog 

Flat coated Retreiver 

Scottie 

Westie 

X 

Profiling … 

1. Thymic Lymphoma b) AKR, NODscid, C58 

2. B cell Lymphoma g) SJL/J (etc) 

3. Plasma cell tumors (myeloma) 

(Harderian, myoepithelioma, c) BALB/c 

Rhabdomyoma etc ) 

4. Lung tumors a) A strains 

5. Mammary tumors d) C3H strains 

6. Mammary Hyperplasia also 

EMT with pituitary tumors 

F) FVB/N 

7. Liver tumors d) C3H, CBA 

8. Cancer Resistant e) C57Bl/6 (DBA, CBA) 

87 

Mouse Pituitary Tumors … 

Adenomas of pars distalis are more common than of pars 

intermedia. 

Aged females. 

Like rat may 

secrete prolactin 

well‐delineated 

Compressive 

angiectatic or 

cyst‐like spaces 

are common. 

88 


E.g. 

Adrenal cortical 

hyperplasia – 

adenoma 

In rats Medullary 

tumors are 

more common 

– NOT little rats 

89 

Other Tumors … 

E.g. 

Thyroid Follicular 

hyperplasia – 

adenoma 

In rats –also C Cell 

tumors 

Mice are NOT little 

rats 

90 

Other Tumors … 

Other Tumors –Skin – subcutis 

Sarcoma, 

fibrosarcoma 

FVB/N > others? 

Ear tags etc. 

Trp53 mutations 

91 

Thoolen, B., R. R. Maronpot, et al. (2010). "Proliferative and Nonproliferative Lesions of 

the Rat and Mouse Hepatobiliary System. . Toxicol Pathol 2010;38:5S-8 1S 

INHAND Nomenclature 

Fig 157. Mouse liver. 

Hemangioma. 


Hemangiosarcoma. 


Hemangiosarcoma. Higher 

magnification of Figure 158. 


Hemangiosarcoma. Higher 

magnification of Figure 159. 


Extramedullary 

hematopoiesis. 


Extramedullary 

hematopoiesis. Myelopoiesis 


Tumor in Chimeras 

92 Copyright © by Society of Toxicologic Pathology 

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Chimera 

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Extragonadal teratoma, 

teratocarcinoma

Teratoma in B6, 129 chimera 

Swollen, fractured? tail 

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5. 5 Mouse Tumors 

Most common /likely 

Lymphoma; Lung; Liver; Mammary; Pituitary etc. 

B6 is pretty resistant 

– is this good for our cancer studies? 

CONCLUSIONS 

EXPECT THE EXPECTED – consider the unexpected 

PATHOLOGY for diagnosis 

– Spontaneous expected vs important or unexpected 

Don’t let expected conditions mess up your research 

– Don’t miss unexpected important phenotypes 

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Also 

Don’t shoot (or fire) the pathologist when 

its not the phenotype you were aiming for 

…. 

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Final Conclusions 

1. Select the best mice for YOUR aims 

2. Expect the Expected 

– Recognize unexpected phenotypes 

3. Strategic Pathology 

– Diagnose problems and unexpected findings 

– Confirm, characterize, validate Phenotypes 

Improve model selection, experimental design, 

data analysis and reporting to achieve robust, 

relevant, reproducible, and ’translatable’ 

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References –Mouse Disease, 

Pathology, Phenotypes 

Barthold, S. W. (2004). "Genetically altered mice: phenotypes, no phenotypes, and Faux 

phenotypes." Genetica 122(1): 75‐88. 

Brayton, C., M. Justice, Montgomery, C. (2001). "Evaluating mutant mice: anatomic pathology." Vet 

Pathol 38(1): 1‐19. 

Brayton C. Spontaneous diseases in commonly used inbred mouse strains. 2006. In Fox. J.G. & al. 

Ed’s. In THE MOUSE IN BIOMEDICAL RESEARCH 2nd Ed. ACLAM series. Elsevier. 

Brayton, C. Treuting, P; Ward, J (2012). Pathobiology of Aging Mice and GEM: Background Strains 

and Experimental Design. Veterinary pathology. 49(1): p. 85‐105. 

Frith, C. H. and J. M. Ward (1988). A COLOR ATLAS OF THE NEOPLASTIC AND NONNEOPLASTIC 

LESIONS OF AGING MICE, Elsevier; out of print. http://www.cldavis.org/ print on demand 

.www.informatics.jax.org/frithbook/chapters/references.shtml 

Maronpot, R. R., G. A. Boorman, et al., Eds. (1999). PATHOLOGY OF THE MOUSE: REFERENCE AND 

ATLAS. Vienna, IL, Cache River Press. 

Keenan, C., et al., Best practices for use of historical control data of proliferative rodent lesions. 

Toxicol Pathol, 2009. 37(5): 679‐93 

Sundberg, J. T. Ichiki. 2005. Handbook on Genetically Engineered Mice. CRC Press 

Ward, J. M., M. R. Anver, et al. (2000). Pathology of Mice commonly used in Genetic Engineering 

(C57BL/6; 129; B6;129; FVB). PATHOLOGY OF GENETICALLY ENGINEERED MICE. M. J. Ward JM, 

Maronpot RR, Sundberg JP. Ames, IA, Iowa 

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Resources ‐ Online 

Frith, C. H. and J. M. Ward (1988). A COLOR ATLAS OF THE NEOPLASTIC AND 

NONNEOPLASTIC LESIONS OF AGING MICE, Elsevier; out of print. 

http://www.cldavis.org/ print on demand 

.www.informatics.jax.org/frithbook/chapters/references.shtml 

INHAND International Harmonization of Nomenclature and Diagnostic Criteria for 

Lesions in Rats and Mice (INHAND) project (http://www.toxpath.org/nomen/) 

MGI Mouse Genome Informatics http://www.informatics.jax.org/ 

– FIND GENES NOMENCLATURE HOMOLOGIES ALLELES REFRENCES 

MMHCC Mouse Models of human Cancer consortium, an initiative of NCI, more at 

http://emice.nci.nih.gov/ 

MPD MOUSE PHENOME DATABASE http://phenome.jax.org/ 

MTB Mouse Tumor Biology Database http://www.informatics.jax.org/mtbwi/index.do 

PATHBASE European mutant mouse pathology database http://eulep.pdn.cam.ac.uk/ 

RENI Registry Nomenclature Information System http://www.goreni.org/ 

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cbrayton@jhmi.edu 2013

Sick - Johns Hopkins Medicine

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