Page 650 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

628 PART IV Specific Malignancies in the Small Animal Patient

12 Sertoli cell tumors, and all three interstitial cell tumors evalu-
ated. Interestingly, staining intensity was stronger in diffuse type
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Sertoli cell tumors and seminomas, similar to findings in another
VetBooks.ir study. 41,55 Results suggest that p53 expression may be an indicator
of tumor aggression; however, further studies should be done to
corroborate this. 41,55
Similar to p53 and proliferation indices, angiogenesis plays
an important role in cancer progression and metastasis. Vascular
endothelial growth factor (VEGF) and microvessel density (MVD)
have been investigated as indicators of the degree of angiogenesis
in multiple human and canine tumor types. VEGF expression and
MVD were higher in seminomas compared with normal testes in
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one study. In addition, both VEGF and MVD were higher in
diffuse seminomas compared with more well-differentiated intra-
tubular seminomas, potentially providing a histologic indicator of
malignant behavior. 57
• Fig. 29.2 Sectioned seminoma in a dog, demonstrating its ivory, homo- The KIT protein or CD117 is a transmembrane protein for
geneous appearance in comparison to a mildly atrophied contralateral a tyrosine kinase receptor encoded by the proto-oncogene c-kit,
testicle. which, when bound to its ligand stem cell factor (SCF), is essential
to the development, proliferation, and maturation of several cell
types, including germ cells. 58–60 Primordial germinal cells express
(proliferating cell nuclear antigen [PCNA], Ki67, and argyro- KIT and migrate to interact with Sertoli cells that express SCF to
philic nucleolar organizer regions [AgNORs]) and TERT expres- guide the differentiation of the primordial cells into gonocytes.
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sion (the catalytic reverse transcriptase subunit of telomerase) have Interstitial cells of Leydig also express KIT and, when stimulated
been interrogated as indicators of degree of malignancy, local pro- by SCF, produce testosterone subsequent to Sertoli cell stimula-
gression, and metastasis with discordant results. 39–44 Investigators tion. 58,61,62 The expression of KIT is maintained by spermatogo-
sought to relate TERT to proliferation indices and p53 expression; nia until differentiation into spermatocytes, making it a useful
however, because PCNA and TERT were expressed in all testicular marker to define primordial germinal cells and early germinal
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tumors, their prognostic potential is limited. Aggressive testicu- cells. 61,63 In human seminomas, immunohistochemical (IHC)
lar tumors did express high levels TERT, p53, PCNA, and Ki67, labeling for KIT and placental alkaline phosphatase (PLAP) is
suggesting these may provide some indication of biologic behav- used to distinguish SE and SS, because SE expresses both KIT and
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ior. Proliferative activity using AgNORs was assessed in canine PLAP whereas SS is negative for both. 64,65 Results in dogs with
seminomas, in which mean AgNOR scores were higher in invasive seminomas have suggested that, like in humans, canine semino-
or diffuse tumors compared with well-differentiated intraductal mas may be differentiated into SE and SS using KIT and PLAP,
seminomas. Results suggest that testicular tumors develop a pro- although the frequency of each subset may affect how relevant
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liferative advantage as they become less differentiated, although the dog is as a model for human seminoma. 21,22,63,66,67 Recent
larger studies should be performed before proliferative indices can histopathologic and IHC studies have suggested that SE may be
be definitively relied on for prognostication in canine testicular rare in dogs, whereas canine SS may be a good model for humans,
tumors. Cyclins, which are intracellular proteins that form com- despite the rarity of SS in men. 66,67 In addition, intratubular germ
plexes with cyclin-dependent kinases to regulate cell-cycle check- cell neoplasia of undifferentiated origin and carcinoma in situ are
points, have also been evaluated in normal and neoplastic testes; frequent precursor lesions of SS in men, but these are infrequently
however, their significance is yet to be determined. 45 identified in dogs. 22,33
The neoplastic cellular environment plays an important role in
tumor invasion and progression, and a few studies have attempted Natural Behavior
to investigate changes in canine testicular tumors. Laminin is an
extracellular matrix protein involved that plays a role in anchor- Most primary testicular tumors in the dog are characterized by
ing cells to the basement membrane. As tumors became more local invasion and rarely metastasize. Regional or distant metas-
invasive, laminin expression became fragmented or lost in Sertoli tasis occurs in fewer than 15% of dogs diagnosed with Sertoli
cell tumors and seminomas, and this correlated with increasing cell tumors or seminomas. 6,32,33,68–74 Interstitial cell tumors very
proliferative activity as assessed by PCNA scoring, Ki67 index, rarely metastasize. Sites of metastasis may include regional lymph
6
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and mitotic index. Connexin 43 is the predominant gap junc- nodes (LNs), eyes, brain, lungs, kidney, spleen, liver, adrenal
tion protein of the testis and plays a role in phenotypic differen- glands, pancreas, skin, and peritoneum. 6,32,68–74
tiation, cell pattern formation, and morphogenesis; and altered Primary testicular tumors can also cause imbalances in sex hor-
expression patterns may contribute to tumorigenesis and progres- mone levels, regardless of the degree of local invasion and pres-
sion. 46–50 Similar to other work, differential alterations in con- ence or absence of metastasis. Sertoli cell tumors can cause signs
nexin 34 expression occur in canine testicular tumors, and its of feminization and more than 50% of affected dogs display signs
expression may aid in differentiating neoplastic Sertoli cells from of estrogen overproduction. 14,25,32,69 Seminomas and interstitial
seminomas. 51 cell tumors are rarely associated with feminization. 75–77 Excess
Mutations of the p53 tumor suppressor gene are common in estrogen can cause signs such as bilateral symmetric alopecia,
both human and canine tmalignancies, and increased p53 expres- cutaneous hyperpigmentation, epidermal thinning, squamous
sion has been associated with tumor progression. 52–56 Nuclear metaplasia of the prostatic epithelium, gynecomastia, galactor-
p53 immunoreactivity was detected in 15 of 20 seminomas, 6 of rhea, attraction of other males, preputial atrophy, atrophy of the