Ch 82 MCT Flashcards
MCT
most common tumour
- precursors originate from CD34+ progenitor cells in bone marrow, migrate to peripheral tissues and differentiate into mature mast cells.
- involved in inflammation and immunoglobulin E (IgE)-mediated immunity.
- granules: histamine, heparin, proteases, chemotactic factors, cytokines, and metabolites of arachidonic acid.
- granules stain with cationic dyes.
- visceral form (disseminated or systemic mastocytosis)
- trunk (42% to 65%), followed by the limbs (22% to 43%)
- Extracutaneous sites: conjunctiva, oral cavity, salivary gland, larynx, nasopharynx, trachea, gastrointestinal tract, ureter, and spine
What breeds are predisposed to MCT?
multiple cutaneous mast cell tumors?
Boxers
Boston Terriers
Pugs
Bull Terriers
Bullmastiffs
Cocker Sp
multiple: Boxers, Pugs, Staffy, Golden Retrievers, and Weimaraners
Etiology
- largely unknown and is probably multifactorial
- genetic factor is likely, considering several breed predisposition
- Stem cell factor (stimulator of differentiation) binds to the growth factor receptor KIT (CD117)
- KIT = tyrosine kinase receptor involved with biologic activities (proliferation, migration, and maturation)
- KIT is encoded by the protooncogene c-kit
- 15% to 50% of mast cell tumors are affected by c-kit mutations
- significantly associated with tumor grade, recurrence and death
WHat mutation is seen in up to 50% of canine MCT?
C-kit
significantly associated with tumor grade, recurrence and death
presentation, degranulation, systemic dz
- Up to 25% of dogs are presented with multiple tumors
- growth rate and clinical appearance associated with histologic grade and prognosis
- dermal or subcutaneous
degranulation
- size fluctuation, edema, erythema, and inflammation (Darier sign, associated with a worse prognosis)
- provoked by manipulation
- paraneoplastic syndromes
- histamine > gastrointestinal ulceration (gastric acid production [H2] receptors, vascular damage, and hypermotility) general GIT signs
- Postoperative delayed wound healing: several studies not found a difference
- heparin > increased bleeding
disseminated (systemic) mastocytosis
- systemic spread of primary cutaneous mast cell neoplasia
- lymphadenopathy, splenomegaly, and hepatomegaly
- Involvement of bone marrow and peripheral blood
- Primary visceral and bone marrow involvement poor prognosis
mets
- regional draining lymph nodes and later in the spleen and liver.
- lungs is highly uncommon
- Multiple cutaneous: may be mets or de novo (px still determined by grade]
Grade
Patnaik
- well-differentiated (grade 1),
- intermediate (grade 2),
- undifferentiated (grade 3).
- metastatic rate (to lymph nodes or distant sites)
- low-grade (grade 1) <10%
- intermediate (grade 2) 2-20%
- high-grade (grade 3) 12-96%
problems with Patnaik
- tumor invasion = dermis and expanding into the subcutis.
- Strict application of this system does not consider well-differentiated tumors originating from the subcutis (which have a better prognosis)
- Large variation in outcome and grading amongst pathologists > inconsistency between grade 1 versus grade 2 among pathologists together with the relatively good outcomes of many grade 2 tumors suggests those grade 2 tumors are “low grade’
Kiupel
- low grade (85% of Patnaik grade 2)
- high grade
- high interobserver consistency
- significant prognostic relevance: MST 690-1452 days versus 110-208 days for low- versus high-grade tumors
significant prognostic factors:
- invasive growth pattern
- Mitotic index
Dx and staging
- diagnosed > 96% through cytology
- Romanowsky-type stains (diff-quik)
- Some undifferentiated mast cell tumors have no clearly staining granules
- grade of malignancy, and thus prognosis, only by histologic grade
- Lymph node status is a prognostic factor for survival, independent of tumor grade
- 15% Kiupel low-grade
- 30% Kiupel high-grade
(WHO) clinical staging scheme
- Controversy about its validity, concerning multiple cutaneous tumors and the term dermis
- Multiple cutaenous automatically categorized as stage 3 and thus poor px (not supprted by literature)
- grade 2 and 3 tumors are by definition not confined to the dermis and could therefore be categorized as stage 3
staging
- FNA/biopsied l.n. even if they are normal in size
- Determination of lymph node metastasis can be tricky because mast cells are present in normal lymph nodes (look for sheets, atypia)
- extirpation recommended for definitive dx and therapeutic
- abdominal ultrasonography with emphasis on evaluation of liver and spleen +/- FNA regardless of appearance
survival
Grade 1/2 low-grade: 700-<1300d
Grade 3/high grade 100-380d
1yr survival 1 100% 2 90% 3 50%
recurrence rates
- known or unknown margin status were 1% for grade 1, 5% to 11% for grade 2, and 19% for grade 3 mast cell tumors
- reported recurrence (or occurrence) of mast cell tumors at other sites in the skin after resection of a primary mast cell tumor 22% to 38% overall (all grades)
Tx considerations
- depeneds on clinical stage, histologic grade, anatomic location
- most important prognostic factor is histologic grade
- Patnaik 1-2 or Kiupel low-grade best treated using wide resection surgery or marginal surgery combined with radiation therapy
- High-grade, high-risk (stage 2), and irresectable tumors treated best using a multimodal approach (wide exicsion or margina with radiation plus chemo)
- improved survival compared to only primary tumor excision with lymphadenectomy of metastatic nodes
surgical margins
- tend to invade and spread into surrounding tissues
- Surgical excision is the therapy of choice for all grades
- Historically, 3 cm of macroscopically normal tissue with the deep margin (fascia > dense collagen/vascular poor tend to behave as biologic barriers)
- lateral margin reocmmendations have been challeneged
1. grade 1 with 1 cm margin (100%) and grade 2 with 2 cm (85-100%) excised
2. A modified proportional margin approach with lateral margins equal to the size of the tumor diameter up to maximum 2cm > 95% excised regardless of grade
Prognostic Factors
Clinical Presentation (-ve)
- darier sign
- Systemic signs associated with viceral
- large tumors >3 cm (vs slow growing, present for >6mths +ve)
tumor location
stains/histo
- unpredictable nature based on histologic grade alone, grade 2 mast cell tumors may be further classified
- nuclear proliferation marker Ki-67 was significantly related to decreased survival time,
- Mitotic index is significantly related to recurrence, metastasis, and survival time
Clinical Stage
- stage 0 or 1 has a better prognosis compared with higher stages (stage 1 usually several years)
- lymph node metastasis at the time of diagnosis significantly shortens survival
- stage 2 treated may have comparable MST to stage 0 (multimidal approach)
margins
- grade 3 carry a poor prognosis (survival < 3 months) after incomplete resection).
- MST of complete not different compared with incomplete resection of grade 2
- only 5% to 23% local recurrence has been reported for grade 2 dirty margin
- 4% local recurrence after complete excision of Kiupel low-grade with no difference bwteen wide and narrow margins
- Kiupel high-grade tumors have a higher chance of local recurrence.
- overall data suggets incomplete margins = higher rate of local recurrence + local recurrence is significantly related to decreased survival time
- low recurrence incompletely excised grade 1 and 2 > cells less atypical than those of high-grade tumors, making it more difficult to distinguish between normal and neoplastic mast cells, tumor chemotatctic agens recruiting normal mast cells
What MCT locations may be associated with a poorer prognosis?
- Preputial
- Scrotal
- Subungal
- Oral and other mms
- Perineal and inguinal sites
- Perioral/muzzle
- Visceral or bone marrow involvement
What special stains can be used for MCT which may help to prognosticate?
IHC of Ki-67 (nuclear proliferation marker)
PCNA
AgNOR using silver-based stains
Radiation Therapy
- most effective therapies for incompletely excised low- to intermediate-grade tumors without metastasis are scar revision or radiation therapy of the wound bed
- median survival time was significantly increased after wide reexcision (2930 days) or radiation therapy (2194 days) compared to no additional local therapy (710 days)
- distal extremity grade 1 and 2 best treated by a combination of marginal resection and adjuvant radiation therapy (alternative to radiacal amputation)
- lymph node irradiation improved outcome for grade 3
chemotherapy
- most studies evaluating chemotherapy lack a control group, lack standardization, include patients with incompletely excised grade 2 mast cell tumors, and include patients that also received other treatments (e.g., radiation).
- high-risk grade 2 mast cell tumors (high mitotic index, lymph vessel infiltration, incomplete margins) for metastasis of grade 3 may warrent chemo
- Oral prednisone > reduce the size of tumors in 20% to 75% of the cases
- generallt poor resposnse rates for singe agent (<27%)
- response rates 47% to 65% for vinblastine/prednisone, vinblastine/cyclophosphamide/prednisone > MST macroscopic disease may be shorter than for microscopic disease
- prolong disease-free interval and survival, it did not prevent development of mast cell tumors at distant sites in the skin in 25% of the cases.
- Chemotherapy-induced toxicity was moderate to severe in 22% to 41% of patients treated with CCNU
electrochemotherapy
histologic grades 1 to 3 were treated with intratumoral application of bleomycin followed by local application of biphasic electrical pulses. The overall response rate was 85%, and the mean estimated time to recurrence was 53 ± 7 month
Tyrosine Kinase Inhibitors
- mutation of the receptor tyrosine kinase KIT, found in 15% to 50%
- methods of testing for such mutations, which in general are relatively insensitive and probably cause an underestimation (so dogs without mutation may repsond to tx)
- masitinib and toceranib
- increased progression-free interval and MST compared to placebo for grade II and III tumors
- Response rate was higher (69%) for tumors with c-kit mutations
- Adverse events (mainly mild to moderate gastrointestinal signs)