Page 90 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

CHAPTER 3 The Pathology of Neoplasia 69

TABLE 3.5 Molecular Features Underlying Grading has been shown to be a sensitive alternative to histopathology for
Criteria LN metastasis needed for staging. 85,86 However, if the cytologic
assessment is negative, histologic evaluation still should be consid-
VetBooks.ir Grading Criteria Underlying Molecular Mechanisms ered. In both processes of tumor grading or tumor staging, these
procedures are useful only if they have been shown to correlate
Cyclins, cyclin-dependent kinases (CDKs),
Mitotic activity
proliferating cell nuclear antigen (PCNA), Ki67, with clinical behavior.
bromodeoxyuridine (BrdUrd), labeling index (LI)/
growth fraction (GF) Assessment of Tumor Margins
Percent necrosis Inflammatory mediators, including eicosanoids
(prostaglandins), cytokines; microvessel density Margin assessment is an essential component of oncologic
(MVD), including vascular endothelial growth specimen review, especially when the surgical goal is curative-
factor (VEGF), thrombospondin-1 (TSP-1), and intent. 1,87 Although several important limitations are associated
hypoxia-inducible factor 1-α with this practice, routine histopathology is the most widely
available method of determining excisional completeness. His-
Invasiveness Matrix metalloproteinases (MMPs), plasminogen
activators (PA), integrin expression, cell adhesion tologic margins are a predictive marker of surgical treatment;
molecules (E-cadherin, N-cadherin) however, margin status does not predict recurrence with absolute
certainty. 1,87,88 Additionally, margin status at a primary site does
Stromal Transforming growth factor beta (TGF-β), platelet- not address the potential for metastases or the likelihood of a
reaction derived growth factor (PDGF), basic fibroblast disease-free state.
growth factor (bFGF), VEGF, MVD mediators
The surgical edge refers to the surgically incised edge/excisional
Nucleolar size RNA transcriptional activity, silver staining nucleolar edge of the biopsy specimen. The gross surgical margin refers to
organizing regions (AgNORs) the region between the surgical edge and the physically palpable
and/or visual mass; typically determined before the surgical pro-
Overall Growth fraction, apoptosis factors (i.e., FasL,
cellularity caspases), tumor doubling time cedure and presumed to be tumor free. Microscopically the histo-
logic surgical margin (histologic tumor-free margin [HTFM]) is
the quantifiable tumor-free tissue between the neoplastic process
and the surgically incised edge. Microscopic margin assessment
typically co-occur and, similarly, morphologic grading criteria are should be performed for both benign and malignant lesions,
likely interconnected (e.g., tumoral necrosis, inflammation, stro- although detailed characterization of the HTFM (e.g., objective
mal response, and invasive growth). 46 measurement, tissue constituents and viability) may be limited
As digital technologies become more readily available, grading to malignancies because recurrence of benign tumors is uncom-
schemes may change. Digitization has the potential to transform mon. Crucial determinants for obtaining accurate surgical margin
previously categorical morphologic criteria into more objective information on the pathology report are (1) specimen handling
and repeatable continuous variables; it also will help assess the and information submitted by the clinician; (2) the method of
value of individual morphologic criteria used to estimate the prog- tissue trimming performed at the laboratory; and (3) observations
nosis. 76–78 Automated computerized morphologic examination is reported by the pathologist. 1
not routinely available in veterinary diagnostic pathology, but it Histologic surgical margins should be interpreted with a
might soon overcome the current limitations. knowledge of the intrinsic limitations of histopathology and fac-
Grading may be supplemented by ancillary diagnostics to pro- tors that influence the pathologist’s interpretation. The clinician
vide a more accurate prognostic estimate. For example, internal is responsible for communicating the surgical goals as they relate
tandem duplications in exon 11 of the c-kit proto-oncogene have to excisional outcomes (i.e., debulking versus curative-intent) and
been linked to tumor grade, survival, and response to tyrosine which tissue edges require microscopic scrutiny. In some cases
kinase inhibitor therapies. 79–82 Measures of tumor growth fraction annotated sketches or images might assist with trimming (regions
(e.g., Ki67 index) have been successfully applied to canine oral selected from the gross specimen at the laboratory for processing
melanocytic tumors, particularly when routine morphologic inter- and microscopic evaluation). Inking is the preferred method of
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pretation offers an ambiguous assessment of the biologic course. identifying a surgical edge because it can be visualized at both the
Recognition of cancer stem cells and an enhanced knowledge of gross and microscopic levels. 5,89 Grossly the surgical ink affects
tumor heterogeneity may continue to influence approaches to regions of the specimen that are selected during trimming for
tumor grading. microscopic examination. Importantly, ink allows the pathologist
The pathologist may assist in staging by assessing tumor size, to identify a true surgical edge appropriately under the microscope
depth of invasion, LN involvement, or confirmation of the neo- (as opposed to artifact) and report the margin as it relates to a
plastic process at distant sites. This information is needed to stage specific gross anatomic region. Surgical ink should be placed only
tumors into WHO’s TNM system (i.e., tumor size and/or inva- on regions of the specimen that are true surgically incised edges
sion; nodal involvement; and distant metastasis). Categories for or areas of specific clinical concern. Ink should also be allowed to
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tumor size and depth of invasion vary according to tumor type. dry according to the manufacturer’s instructions (approximately
In human melanoma the Clark and Breslow scales are used to 15 minutes) before fixative immersion. Even under ideal condi-
determine tumor size and depth of skin involvement. In human tions, inking can be associated with a number of artifacts that may
bladder cancer, tumor staging is largely based on the depth of influence the histologic interpretation. Continuous suturing of
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3,5
tumor invasion into the bladder wall. Similar concepts might postexcisional specimens might mitigate artifacts associated with
be applicable for veterinary patients with tumors such as canine tissue alignment and cohesion. 91
urothelial carcinoma and feline gastrointestinal lymphoma. 10,84 Histologic surgical margin outcomes are influenced by the
Cytologic assessment (i.e., fine-needle aspirate) of draining LNs method used to trim specimens at the laboratory. 1,92,93 One study