Page 628 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

606 PART IV Specific Malignancies in the Small Animal Patient

correspond with important clinicopathologic parameters such as of greater than 3.79 Despite these discrepancies, several studies
growth rate, size, and histotype. 61,62 A complete review of the bio- have documented that tumor expression of ER and PR is associ-
ated with a more favorable outcome.
Endocrine therapy is
74,76,77
logic and molecular aspects of MGT carcinogenesis is beyond the
VetBooks.ir scope of this chapter, but recent reviews provide more complete recommended to all women with ER-positive tumors, regardless
63,64
of intensity of staining, and results in significant improvement in
information.
The entire mammary chain is exposed to growth factors and survival when used in the adjuvant setting. 80–85 In addition to the
sex hormones, resulting in a field carcinogenesis effect. Conse- presence of HRs, the overexpression of human epidermal growth
quently, most dogs develop tumors in multiple glands. 9,14,15,65–67 factor receptor-2 (HER-2/erb-2), a member of the epidermal
Histologic progression with increasing tumor size is often noted growth factor receptor family involved in signal transduction
in dogs with multiple tumors and areas of transitions such as car- pathways that regulate cell growth and differentiation, may also
cinoma in situ (CIS) can be seen in benign tumors. 15,65 This pro- provide clinical and prognostic insight and therapeutic oppor-
vides direct evidence that benign and malignant MGTs are not tunities in MGTs. Overexpression or amplification of HER-2 is
separate entities; instead, they are part of a biologic and histo- found in 20% to 25% of all human BC patients and is associated
pathologic continuum in which the malignant invasive carcino- with aggressive behavior, resistance to hormonal therapy, and a
mas are the end stage of the process. Earlier publications support poor prognosis. 86–88 HER-2 overexpression has also been docu-
this hypothesis and document associations between tumors of mented in canine MGTs using the same HercepTest scoring sys-
benign and malignant histology. For instance, dogs with carcino- tems used in human BC; positive staining has ranged from 17%
mas often had concurrent benign tumors of the same cell type to 48% in malignant tumors. 89–94 HER-2 staining was associ-
and dogs with benign MGTs were at increased risk for develop- ated with negative histologic features and short survival times
89
ing subsequent malignant tumors. Furthermore, risk was even (STs) according to one of these studies but, contrary to the
66
higher in dogs diagnosed with CIS or carcinomas. 15,65,67 Evidence human studies, HER-2 expression was associated with improved
of histologic progression has also been reported in which a high survival in two other independent studies. 90,91 Discrepancies can
incidence of CIS and intraepithelial lesions with atypia was noted be related to IHC protocols and scoring systems, which are still
adjacent to invasive carcinomas. 65,68 There are likely regional vari- controversial in human BC. Recently preanalytical, analytical,
ations in terms of exposure resulting in a range of histopathologic and postanalytical guidelines have been suggested to test HER-2
95
and clinical changes. Some tumors may never change and remain expression in canine MGTs. They suggest 6- to 48-hour for-
small and benign whereas others progress and become malignant malin fixation, evaluation of the invasive portions of the tumor,
and many develop new tumors in other glands. This suggests that and threshold positive immunostaining to be greater than 30%
canine MGTs provide unique comparative opportunities to study of cells with complete membrane staining. 95
mammary carcinogenesis and progression with direct applications Information about HR and HER-2, added to data on the
to human BC research. expression of luminal versus basal cell differentiation mark-
ers and Ki67, allows for the molecular classification of human
Tumor Hormone Receptors/Molecular-Based BC. More precisely, IHC-based surrogates of gene expression–
Classification: Prognostic, Clinical, and based molecular subtypes are routinely applied. In human BC,
the IHC subtypes include luminal A (high HR, HER-2–, low
Therapeutic Implications Ki67, luminal markers +, basal markers +/–), luminal B (low
Hormonal exposure plays an important role in MGT develop- HR, HER-2+/–, any/high Ki67, luminal markers +, basal mark-
ment and many tumors, specifically tumors of epithelial origin, ers +/–), HER-2-overexpressing (HR–, HER-2+, any Ki67, lumi-
express hormone receptors (HRs), suggesting continued hor- nal markers +/–, basal markers +/–), and triple-negative (HR–,
monal influence and dependence. Benign tumors are more likely HER-2–, any Ki67, luminal markers +/–, basal markers +/–).
than malignant tumors to retain HRs, both estrogen receptors The latter includes the molecular basal-like tumors which are
(ERs) and progesterone receptors (PRs). 69–73 The HR status is triple-negative for receptors (ER, PR, HER-2) and express basal
also influenced by age and hormonal status: dogs that are intact, markers (CK5, CK6, CK14, CK17, SMA, calponin, vimentin,
younger, and in estrus are more likely to have receptor-positive and p63) and not luminal markers; the normal-like subtype,
tumors than dogs that are spayed, older, and anestrous. 73–75 Fur- which is negative to all markers and shows a adipose tissue sig-
thermore, the HR expression is inversely correlated with tumor nature; and the claudin-low subtype, which is also triple-negative
size and histopathologic differentiation; larger tumors and (ER, PR, HER-2) and, regardless of basal markers, expresses low
undifferentiated or anaplastic tumors are less likely to express claudin and high vimentin. 96–100
receptors than tumors with more differentiated histology, reflect- In women, these subtypes are associated with different clinical
ing a biologic drift toward hormone independence and corre- outcomes, ranging from the best prognosis for luminal A tumors
sponding with aggressive histology and clinical behavior. 74,76,77 to the worst prognosis for two of the triple-negative subtypes
HR expression analysis is most commonly performed by immu- (basal-like and claudin-low). 100 In women with BC, treatment is
nohistochemistry (IHC). Results from various studies are quite determined using these molecular signatures, histopathologic sub-
disparate, especially in terms of ER-alpha positivity in malignant type, histologic grading, and clinical staging. 99
tumors, and range from 10% to 92%. 69–74,76–79 These variations Recently a few studies have attempted a molecular classifi-
may in part be due to differences between study populations cation of canine MGTs by applying the same human BC IHC
91
(tumor size, OHE status, tumor types) and the fact that IHC panels. 91,92,94 In one study, this classification was prognostic
methods vary and, up until recently, have not been validated with the basal-like phenotype significantly associated with shorter
or tested for their ability to predict response to hormonal ther- disease-free interval (DFI) and overall survival time (OST); how-
apy. A prospective randomized trial on the effect of OHE in ever, the results differ between studies and highlight the need for
79
dogs with mammary carcinoma determined the threshold posi- continued investigations and standardizing the IHC protocols.
tive immunostaining of both ERs and PRs to be an Allred score This represents the first and crucial step toward using results