Mammary tumors

Question 1

What are the 3 major risk factors for mammary carcinoma?

Answer 1

age, breed, hormonal exposure

Question 2

Spayed prior to 1st estrus ___% risk; 2nd estrus __%; 3rd estrus __%

Answer 2

0.5, 8, 26

Question 3

No protective effect of spay after ___ years old

Answer 3

4

Question 4

Recent study found that OHE with benign tumor removal decreases the risk of developing additional tumors (these were in older dogs, confirming that hormonal deprivation even late in life ê risk of tumor development)

Randomized controlled trial 42 dogs with benign tumors – OHE reduced risk by 50%

“New mammary tumor(s) developed in 27 of 42 (64%) intact dogs and 15 of 42 (36%) ovariohysterectomized dogs”

Question 5

Hormonal therapy ____ risk

Treatment with progestins to prevent estrus increases risk by ___x

Progestin-only treatment tends to produce ___ tumors

Estrogen-progestin combinations increase risk for ____ tumors

Answer 5

increases

2.3

benign

malignant

Question 6

Peak incidence at age ___

Tumors in dogs ___ rarely malignant

Risk of malignancy increases with __

Mean age: benign ___ yrs; malignant ____ yrs

Answer 6

10

<5

age

7-9, 9-11

Question 7

List 6 small breeds predisposed to mammary carcinoma?

Answer 7

poodles, chihuahua, dachshund, maltese, Yorkie, cocker spaniel

Question 8

Large breeds predisposed to mammary carcinoma

Answer 8

English springer spaniels, Brittany spaniel, English setter, German shepherd, pointers, Dobie, boxier

Question 9

Evidence for a a genetic risk:

Breed risk is regional (increased risk for boxers in Europe, decreased in USA)

Risk is associated with genetic lineage (some beagle lines have increased risk while others are decreased)

Human germline mutations in BRCA1 or BRCA2 confer an 85% cumulative lifetime risk

Question 10

Minor factor associated with mammary carcinoma?

During puberty (9-12 months) being overweight increases risk (true in humans too)

Being underweight during the same time period is protective

Associated with decreased sex-hormone binding globulins à increased free estrogen, and increased aromatase enzyme which produces estrogens from androgens

Cancer-protective effect of being under-weight is most significant in the first year of life

Answer 10

Obesity

Question 11

Role of estrogen and progestins in cancer:

• Estrogen and progesterone increase epithelial cell proliferation
• Estrogen is directly genotoxic, inducing mutations and induction of aneuploidy independent of estrogen receptor
• Progesterone is tumorigenic via increased production of GH and expression of GH receptors
• GH — IGF1 — proliferation and survival of mammary epithelium
• Documented in human breast cancer carcinogenesis

Malignant tumors have significantly higher tissue concentrations of GH, IGF-1, progesterone, and 17B-estradiol than benign tumors

Question 12

Field effect: entire mammary tissue exposed to hormones à most dogs develop tumors in multiple glands

Benign and malignant tumors are on a spectrum:

benign tumor à carcinoma in situ à carcinoma

Areas of carcinoma in-situ present in benign tumors (suggesting zones of transition)

Dogs with benign tumors are at increased risk for having malignant tumors

Dogs with malignant tumors often have concurrent benign ones

Question 13

_____ plays an important role in mammary gland tumor development

Answer 13

Hormone exposure

Question 14

____ tumors more likely than _____ tumors to retain hormone receptors (HRs)

Answer 14

benign, malignant

Question 15

Dogs that are younger, intact, and in estrus more likely to have tumors with ____ expression (“receptor-positive”)

Answer 15

HR

Question 16

Larger, anaplastic, poorly differentiated tumors less likely to be ____ (hormone independence à aggressiveness)

Answer 16

receptor-positive

Question 17

Threshold of expression of ER or PR to determine “receptor positivity” defined as an Allred score >3.79

Question 18

ER

• ____ correlated with malignancy

ER+ breast cancers susceptible to ER receptor antagonists or aromatase inhibitors

____ER receptor antagonist used in humans?

• Side effects high in canines prevents use; OHE/OVE more effective

Answer 18

Lack of expression

Tamoxifen

Question 19

Her-2/neu (EGFR family)

• Overexpression in human breast cancer associated with ___ prognosis
• ____% of cases over-express

Studies in dogs have shown discordant results

Answer 19

Poor

20-25%

Question 20

Target for Her-2/neu

Answer 20

• Herceptin / trastuzumab
• Humanized monoclonal antibody against ECD of HER2 transmembrane receptor
• Single agent efficacy is poor, but combined with chemotherapy, efficacy approaches 70%

Question 21

GH/GHR

Answer 21

Progestin effects are mediated through increases in GH and GHR

Question 22

IGF-1

• GH increases proliferation of mammary cancer via IGF-1 signaling

Significantly higher levels of GH and IGF-1 in malignant tumors

Question 23

Common location for mammary gland tumors?

Answer 23

Caudal mammary glands

Question 24

Most dogs are _____ at presentation

Answer 24

clinically healthy

Question 25

5 features of inflammatory mammary CA?

Answer 25

Painful and extensive local disease Metastatic disease is common Usually systemically sick No good treatment options Very poor prognosis

Question 26

Mammary Carcinomas -- See table 28.2 (several, both simple and complex) Carcinoma in situ commonly diagnosed in humans, rarely in dogs due to less frequent early detection In addition to mammary carcinoma, can also see SCC, adenosquamous carcinoma, mucinous carconima, lipid-rich carcinoma, spindle cell carcinoma

Question 27

Mesenchymal/Carcinoma * 4 most common are? * How does metastasis occur? Common location?

Answer 27

OSA, chondrosarcoma, fibrosarcoma, hemangiosarcoma Metastasis is hematogenous most often to lungs

Question 28

Carcinosarcoma * Malignant mixed mammary tumor * Uncommon primary neoplasm * Has cells of epithelial and mesenchymal origin, both neoplastic * Most often presents as carcinoma and osteosarcoma * Epithelial component mets via lymphatics to regional LN, lungs; mesenchymal mets via hematogenous spread to lungs

Question 29

Hyperplasia/dysplasia/Neoplasia of the nipple * Ductal adenoma and carcinoma are rare and only involve the nipple * Nipple enlarged and firm * Histopathology mimics ductal gland carcinoma * Carcinoma with epidermal infiltration = Paget-like, mimics Paget’s disease in women

Question 30

Prognosis is best for adenosquamous (\_\_\_\_ mo), comedo-(\_\_\_ mo), solid (\_\_\_mo) ## Footnote Prognosis for anaplastic

Answer 30

18 month, 14 month, 8 month 3 month

Question 31

Sarcomas and Carcinosarcomas tend to be aggressive and have poor prognosis Many dogs have \>1 tumor, prognosis is determined based on the MOST AGGRESSIVE tumor (which is often the largest)

Question 32

Prognosis Tumor Size Stage 1 – \_\_\_cm, Stage 2 – \_\_\_\_cm, Stage 3 - \_\_\_\_cm, Stage IV – \_\_\_involvement Tumor prognosis changes gradually with \_\_\_\_ Size of tumor is irrelevant if lymph node involvement

Answer 32

Stage 1 – 0-3cm, Stage 2 – 3-5cm, Stage 3 - \>5cm, Stage IV – LN involvement Size

Question 33

Prognosis Lymphatic involvement?

Answer 33

For carcinomas, local lymph node involvement is highly prognostic Lymphatic micro-metastases (clusters from 0.2-2.0mm) do not predict worse outcome

Question 34

The largest contributor to prognosis with respect to stage is?

Answer 34

LN involvement

Question 35

\_\_\_% of patients with one malignant tumor excised via lumpectomy develop a second tumor (survival impact unknown)

Answer 35

70%

Question 36

Dogs commonly (58% in on study of 99 intact dogs undergoing regional mastectomy) develop another tumor on the ipsilateral side (more common when initial tumors are malignant)

Question 37

Radical mastectomy is associated with \_\_\_% post-operative complication rate

Answer 37

77%

Question 38

\_\_\_\_ recommended for aggressive tumors Reduces risk of recurrence by \_\_\_% and reduces risk of other ovarian/uterine diseases

Answer 38

OHE 50%

Question 39

What is recommended with single tumor?

Answer 39

wide excision with sufficient margins to be clean is sufficient (2cm margins and 1 fascial plane is recommended for large tumors)

Question 40

Multiple tumors or LN involvement?

Answer 40

chain mastectomy or bilateral chain

Question 41

Complete excision or recut should be pursued if incomplete margins as complete margins have found significant benefit over incomplete (MST 22.8 vs 15.4 mo; or 872 vs 70 days, in 2 separate studies)

Question 42

What is not recommended for inflammatory mammary carcinoma?

Answer 42

Surgery

Question 43

When is systemic therapy recommended? List 3 reasons when you would recommend?

Answer 43

Recommended if high risk tumor, but actual benefit is questionable \>3cm, carcinoma LN involvement

Question 44

Hormonal Therapy * Surgical OHE/OVE is most direct method * ER modulators, aromatase inhibitors, LHRH-agonists are also mechanisms to reduce estrogen effects * Tamoxifen has significant side effects in canines and not recommended * Progesterone receptor-blocker (aglepristone) showed improved DFI * OHE at the time of surgery or within 2 years prior showed a survival benefit * A recent study found that for HR+ dogs, a modest improvement was seen for dogs undergoing OHE (not statistical), and a significant improvement for dogs with grade II tumors or high median peri-surgical serum estrogen

Question 45

Chemotherapy * No clearly established benefit in dogs in several under-powered studies of doxo, gemzar, carbo, docetaxel, and mitox * ______ with or without chemo have been shown to prolong survival in grade III mammary ca, and in inflammatory mammary carcinoma * Chemotherapy for primary mammary OSA has a benefit based on one retrospective study * A prospective randomized trial established significant improvement in dogs with grade II or III tumors treated perioperatively with desmopressin, hypothesized to be mediated through improving hemostasis and preventing cancer cells from accessing the vasculature during surgery * See table 28.6 for guidelines for systemic therapy

Answer 45

NSAIDs

Question 46

Feline mammary tumor * ___ most common tumor in cats after lymphoma and skin tumors * Most feline mammary tumors are \_\_\_\_\_ * \_\_\_\_expression of ER and PR (consistent with malignancy) * ____ % are malignant * _____ metastasis more common in cats than dogs at presentation * Large tumors can become ulcerated and inflamed

Answer 46

3rd aggressive Low 85-95% LN

Question 47

Major risk factors for feline mammary CA?

Answer 47

age, breed, hormone exposure

Question 48

Age as risk factor for feline mammary CA? Typical age for presentation?

Answer 48

older cats, starting at 7-9 years and increasing with age

Question 49

What feline breed is affected at younger age? Risk plateus at what age?

Answer 49

Siamese are significantly younger when diagnosed; risk plateaus at age 9

Question 50

Hormone Exposure: Sexually intact cats have \_\_\_x higher risk than spayed cats

Answer 50

7

Question 51

Feline mammary tumors ## Footnote Protective effect of spay diminishes precipitously after ___ years Risk decreases by ___ % if OHE \< 6 mo Risk decreases by \_\_\_% if OHE 7-12 mo Risk decreases by \_\_\_% if OHE 13-24 mo

Answer 51

2 years 91% 86% 11%

Question 52

\_\_\_ does not alter risk for feline tumors? Treatment with\_\_\_\_ increases risk (benign\>malignant), with increased exposure leading to increased risk of malignancy Rarely occurs in males, but risk higher for males exposed to progestins

Answer 52

Parity Progestins

Question 53

Risk of developing mammary gland tumors in cats is related to _____ but latency period longer for cats than for dogs Most feline mammary carcinomas are ___ and ____ negative, consistent with higher rate of malignancy and aggressiveness on cats vs dogs Normal mammary tissue and dysplastic lesions express both ER and PR and this tends to wane with malignancy Fibroepithelial hyperplasia is progestin-induced and can be cured by OHE or antiprogestins

Answer 53

hormonal exposure ER, PR

Question 54

Clinical Presentation, Diagnostics, Staging of Mammary Tumors in Cats Generally mature cats that are intact or late spay Most cats ____ % have \>1 tumor at presentation Which glands are susceptible? Local LN’s may or may not be affected Inflammatory mammary carcinoma is rare and similar in course to dogs

Answer 54

60% All glands susceptible; one study says caudal more common

Question 55

Feline mammary tumor ## Footnote \_\_\_\_% malignant with aggressive behavior, lymphatic invasion and LN metastasis Mammary carcinomas in cats are associated with high percentage of triple-negative, frequent expression of both basal cytokeratins and vimentin, and have the worst prognosis

Answer 55

85-95%

Question 56

Feline mammary tumor Prognosis for G1? G2? G3?

Answer 56

Grade relationship to prognosis (two systems): G1 31-36mo; G2 14-18mo; G3 8-6mo

Question 57

List 4 important prognostic factors in cats?

Answer 57

Tumor size, LN status, breed, and age

Question 58

Feline Prognostic Factors: Tumor size: * 2cm: MST \>3 years with sx alone * 2-3cm: MST 2 years * \>3cm: MST \<6 month Lymph node status: LN metastasis significantly _____ prognosis Breed Purebred cats have\_\_\_ prognosis \_\_\_\_ breed has poorer prognosis Age (+/-) Studies bias for older cats having more progressed tumors Prospective study found no difference according to age based on \> or \< 10 yrs

Answer 58

* 2cm: MST \>3 years with sx alone * 2-3cm: MST 2 years * \>3cm: MST \<6 month decreases poorer Siamese

Question 59

Treatment – Feline Mammary Tumors Recommended surgery? PFS for bilateral vs. unilateral Adjuvant chemotherapy is recommended as it increases disease-specific survival. MST? Aggressive LN assessment and removal if involved is recommended Fibroepithelial hyperplasia: Treat with OHE or hormone management

Answer 59

Chain mastectomy or Bilateral chain mastectomy Bilateral PFS 542 days vs unilateral 289 days With adjuvant chemo - MST 1998 vs 414 days for cats with unilateral mastectomies

Question 60

Feline mammary tumor ## Footnote Owing to low HR expression, hormone therapy not likely to be effective Retrospective studies of cats with macroscopic or metastatic disease showed 40-50% ORR from combo DOX-Cytoxan Recent studies of adjuvant chemo suggest DOX-based protocols increase survival and disease-specific survival