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WHO Clinical Stage There is problems with current staging, and the usefulness of WHO is being questioned. Stage III is vague, and combines multiple cutaneous nodules with large infiltrating tumor. There was a presumption that multiple tumors represent systemic metastasis vs. de novo MCT. IN addition, the diagnosis of metastasis based on presence of mast cells in LN FNA, but mast cells are also present in healthy animals. There is also questionable value of buffy coat smears and bone marrow in staging.
Histologic Classification: 3-Tiered
Grade 1: clearly defined cytoplasmic boundaries with regular, spherical or ovoid nuclei, rare or absent mitosis, abundant large deep staining cytoplasmic granules
Grade 2: closely packed cells with indistinct cytoplasmic boundaries, N:C ratio lowers than anaplastic type, infrequent mitoses, and more granules that anaplastic type
Grade 3: highly cellular, frequent mitoses, undifferentiated cytoplasmic boundaries, nuclei irregular in size and shape, sparse cytoplasmic granules
Histologic grade is a prognostic for biologic behavior
and clinical outcome, and an accurate predictor for metastatic behavior. Low grade: <10%, Intermediate grade: low to moderate, High grade: 55-96%. Metastasis is typically to local LN, liver and spleen, bone marrow.
Mitotic Index (MI)
Mitotic Index is an indirect measure of cell proliferation based on number of mitotic figures, and is a strong prognostic factor. It can be performed during routine histology and is easier than other proliferation markers that require additional immunohistochemical staining (AgNOR, Ki-67)
Romansik 2007, Vet Path, 148 dogs: MI was significantly increased with grade, but there was no association
MI and tumor recurrence. MI was associated with metastasis and survival:
• <5/10 HPF, MST 70 mos.; >5/10 HPF, MST 5 mos.
• MI associated with metastasis and survival
• <5/10 HPF, MST 70 mos., >5/10 HPF, MST 5 mos.
• <5/10 HPF, MST 70 mos., >5/10 HPF, MST 5 mos.
• <5/10 HPF, MST not reached, >5/10 HPF, MST < 2 mos.
Note MI not consistent from study to study & expect that the cutoff will continue to be refined as more studies evaluate mitotic index
Molecular prognostic factors: Key findings
Increased Ki67 and AgNORS both significantly associated with decreased survival. MCT with aberrant KIT localization or ITD c-KIT mutations are associated with increased cell proliferation. Multivariable analysis showed Ki67 were significantly associated with incidence
An Urban Experience
& rate of subsequent tumor occurrence at original tumor site, rate of MCT at distant site
The new 2-tiered grading system
Unfortunately there is inter-observer variation among pathologists, and pathologists tend to opt for grade
2 when it is borderline between grade 1 & 2. If more pathologists are calling tumors grade 2, the prognostic value is weakened. Based on the original work by Patnaik, there is ~ 50/50 chance of 5 year survival for grade 2 tumors
A 2 tiered system had been developed and is based
on the number of mitoses (< or > 7), presence of multinucleated cells or bizarre nuclei, and karyomegaly (increased nuclear size). High grade tumors significantly associated with shorter time to metastasis mast cell tumor associated mortality, shorter overall survival time. MST for high-grade MCT < 4 months vs. > 2 years for low-grade MCT
This system is still relatively new and should continue to be validated in future studies.
Other diagnostics:
Buffy coats have been used historically but are unreliable. There can be high number of false positives with inflammatory skin disease, parvovirus, regenerative anemia, traumas, other cancers (McManus 1999)
Spleen and liver cytology: According to Finora, 2006, routine FNA of normal liver and spleen on AUS is not useful but then another study concluded cytology was indicated whether AUS is normal or abnormal (Stefanello 2009).
Treatment
Surgery: Surgery All that you need?
Surgery is the ideal treatment in areas amenable to wide resection. The recommendations for margins
have historically 3 cm, but 2 cm lateral margins may be adequate for most (Simpson 2004). For small and lower grade, extensive deep margins are just as crucial: 1 fascial plane deep, 4 mm deep margins. The majority of naïve dermal MCT are intermediate or low grade will be cured with surgery alone, provided site is amenable.
Location: In some locations, wide margins often not possible, i.e. distal limb. In my opinion, amputation is probably too aggressive. But further therapy will likely be needed after surgery. Post-operative options include external beam RT, scar revision, and chemotherapy
Surgery and margins Histologic assessment of margins may be unreliable. 37.5% recur with clean margins, and 36% have no recurrence with incomplete margins. In Seguin 2001: grade 2 MCT with clean excision, only 5% completely removed grade 2 recur, 5% metastasized, and 11% developed 2nd MCT. Note that microscopic
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