Veterinary Surgical Oncology. Группа авторов

grade I and grade II and grade II and grade III tumors.

      The limitations of the Patnaik grading system prompted development of novel grading systems using mitotic index, argyrophilic nucleolar organizer regions (AgNOR), and Ki67 proliferation markers to help differentiate between grade II MCTs with a poor and good prognosis (Maglennon et al. 2008; Romansik et al. 2007; Scase et al. 2006).

      A two‐tier grading system for MCTs proposed by Kiupel et al. (2011) has been validated and widely adopted by veterinary pathologists and MCTs are frequently reported with grading according to both these systems. The Kiupel system uses mitotic figures, multinucleated, bizarre nuclei, and karyomegaly for grading criteria. Kiupel graded high‐grade MCTs are significantly associated with shorter time to metastasis or new tumor development, and shorter survival time. The median survival time was less than four months for high‐grade MCTs but more than two years for low‐grade MCTs.

      Dogs with high‐grade Kiupel and Grade III Patnaik MCTs were significantly more likely to have metastases (mainly lymph node metastases) at the time of initial diagnosis than low‐grade or Grade II or I MCTs (Krick et al. 2009; Weishaar et al. 2014). Combining histologic grade with clinical stage information provides a more accurate biological behavior prediction than either parameter alone (Stefanello et al. 2015). Prognosis should not rely solely on histologic grade, regardless of the grading system used, but should also consider the results of clinical staging. Dogs with Stage 1 high‐grade tumors treated surgically can have a prolonged survival time (Moore et al. 2020).

       Mitotic Index

      Mitotic index (MI) is an indirect measure of cellular proliferation indices and directly correlates with histologic grade; it is a strong predictor for overall survival. Dogs with cutaneous MCTs with a MI of 5 or less had a significantly longer survival time than those with a MI greater than 5, regardless of histologic grade (Romansik et al. 2007; Berlato et al. 2015). Mitotic count is also prognostic among dogs with a Kiupel high‐grade MCT (Moore et al. 2020).

       Proliferation Indices

      Indicators of cellular proliferation can provide prognostic information about the likelihood of MCTs recurring locally and help differentiate the prognosis of grade II MCTs (Séguin et al. 2006). The three most commonly used cellular proliferation indices are AgNORs, proliferating cell nuclear antigen (PCNA), and number of Ki67‐positive nuclei. Increasing AgNOR and PCNA scores were significantly associated with a shorter progression free interval (Gill et al. 2007). A Ki67 index of greater than 1.8% is a significantly prognostic indicator for poorer survival for grade II MCTs. A higher Ki67 index is also a negative prognostic factor, independent of grade (Scase et al. 2006; Maglennon et al. 2008; Berlato et al. 2015; Smith et al. 2017).

      The KIT protein is a tyrosine kinase receptor that is a product of the c‐KIT proto‐oncogene. Mutations in c‐KIT result in aberrant cytoplasmic expression of KIT in 9–30% of canine MCTs, with high‐grade tumors more likely to have a mutation. Immunohistochemistry protocols for the detection of the KIT receptor expression are well established. Increased expression of KIT in the cytoplasm of neoplastic mast cells is a strong indicator of increased risk of local tumor recurrence and a decreased survival time (Kiupel et al. 2004).

      Histologic panels that employ multiple markers are now available at various veterinary pathology laboratories to facilitate prognostication, especially for grade II MCTs.

      Clinical Stage

      The WHO staging system for cutaneous MCT (Table 4.2) has been reported to be prognostic for tumor‐free time and survival time with surgical MCT treatment (Turrel et al. 1988).

      The presence of lymph node metastasis (WHO stage II disease) has been shown in multiple studies to be associated with a poorer prognosis compared to stage I disease (Murphy et al. 2006; Hume et al. 2011; Turrel et al. 1988; Krick et al. 2009). The lymph node metastasis classification system (HN0‐HN3) is helpful to be more precise regarding the prognostic significance (Weishaar et al. 2014). Dogs with grade III primary cutaneous MCTs are more likely to have metastatic MCT in regional lymph nodes (Krick et al. 2009). Dogs with lymph nodes affected by metastatic disease that are treated with either surgery or radiation have prolonged survival time compared to untreated lymph node‐positive dogs (Hume et al. 2011; Bae et al. 2020). A different study contradicts this finding for Grade 2 MCTs, showing that positive lymph node status does not adversely affect survival time (Baginski et al. 2014). Dogs with stage IV disease at presentation have a very poor prognosis (Pizzoni et al. 2018).

      Size

      Dogs with MCTs > 3 cm in maximum diameter have a shorter median survival time than dogs with tumors <3 cm diameter (Hahn et al. 2004; Hume et al. 2011; Stefanello, Buracco et al. 2015; Moore et al. 2020).

      Anatomical Location

      Various anatomical sites for cutaneous MCT have historically been associated with a poor prognosis. These include MCT located in the scrotum, muzzle, and pinnae. Prognosis is correlated more with grade rather than anatomic location and these anatomical locations often have a higher proportion of high‐grade MCTs and more limited wide resection options.

      Mast cell tumors are the most common type of cutaneous scrotal tumors diagnosed in dogs (Trappler et al. 2014; Smiech et al. 2018). MCTs located in the inguinal, perineal, or scrotal regions were previously reported to have a poorer prognosis compared to other cutaneous locations (Turrel et al. 1988). More recent studies have refuted this finding and concluded that when MCTs in these locations that are treated appropriately have survival times and tumor‐free intervals equivalent to other cutaneous locations (Cahalane et al. 2004; Sfiligoi et al. 2005). The scrotum, inguinal area, and axilla are however reported to be the anatomical locations with highest incidence of high‐grade MCTs (Reynolds et al. 2019). Scrotal ablation and evaluation of the inguinal lymph nodes are recommended for treatment of scrotal MCTs.

      A retrospective study of 24 dogs with MCTs located in the muzzle region identified this location as a site for biologically aggressive tumors with higher regional metastatic rates than previously reported for MCTs in other sites (Gieger et al. 2003). Another study found that dogs with tumors located on the extremities had a longer tumor‐free interval than dogs with MCT located on the trunk (Turrel et al. 1988).

      MCTs of the pinnae have also been reported to have a poor prognosis. A prolonged disease‐free interval without local recurrence may be achieved with local excision of grade 1 and 2 MCTs of the pinnae. Animals with grade 3 MCTs of the pinnae, however, are reported to have a poor outcome with short times to local recurrence and median survival time of 10 months (Schwab et al. 2014).

      Multiple Cutaneous MCT

      Presentation with multiple cutaneous MCTs occurs in 9–21% cases (Murphy et al. 2004, 2006; Mullins et al. 2006). Boxers, Golden retrievers, and Labrador retrievers have been identified as breeds at increased risk of developing multiple cutaneous MCTs (Thamm et al. 1999). Older dogs are more likely to present with multiple cutaneous MCTs (Kiupel et al. 2005). Multiple cutaneous MCT presentation was originally considered a poor prognostic sign and is designated stage III on the WHO staging scheme. Several studies have demonstrated that there is no difference in survival times for single vs. multiple cutaneous MCT (Murphy et al. 2006; Thamm et al. 1999). Dogs with multiple cutaneous MCTs have a low rate of metastasis and a good prognosis for long‐term survival with adequate excision of all MCTs (Mullins et al. 2006). Each individual MCT should be treated as a de novo lesion.

      Subcutaneous MCT

      Mast cell tumors that are strictly subcutaneous (tumors that do not involve the cutaneous layer at all) are their own clinical entity. Overall, subcutaneous MCTs have a relatively good prognosis with