JPC SYSTEMIC PATHOLOGY

INTEGUMENTARY SYSTEM

October 2022

I-N21

 

SLIDE A:

Signalment (JPC # 1957907):  Age and breed unspecified dog

 

HISTORY:  None

 

HISTOPATHOLOGIC DESCRIPTION:  Haired skin and subcutis:  Expanding the dermis and subcutis, elevating the overlying epidermis, separating and surrounding adnexa, skeletal muscle fibers, and collagen bundles, and extending to the margins of the submitted tissue is an unencapsulated, poorly-circumscribed neoplasm composed of sheets of neoplastic round cells (mast cells) on a preexisting collagenous stroma. Neoplastic cells have distinct cell borders, moderate amounts of amphophilic cytoplasm that occasionally contains fine basophilic granules, a centrally located, round nucleus with coarsely stippled chromatin and 1-2 distinct nucleoli.  Anisocytosis and anisokaryosis are mild, there is 1 mitotic figure per 2.37mm² and no trinucleated cells are observed. Scattered throughout the neoplasm are moderate to high numbers of eosinophils and fewer lymphocytes, plasma cells, and hemosiderin-laden macrophages. The overlying epidermis has mild orthokeratosis. Within the dermis, there is increased clear space (edema) and mild dilation of lymphatics. 

 

SLIDE B: Luna mast cell stain:  Neoplastic cells contain numerous intracytoplasmic metachromatic granules.

 

MORPHOLOGIC DIAGNOSIS:  Haired skin and subcutis: Mast cell tumor, low grade, breed unspecified, canine

 

SLIDE C:

Signalment (JPC # 2924576):  13-year-old Standardbred gelding

 

HISTORY:  A subcutaneous mass on the right flank

 

HISTOPATHOLOGIC DESCRIPTION:  Subcutis (per contributor): Infiltrating, separating, and surrounding collagen bundles is an unencapsulated, paucicellular, poorly demarcated neoplasm composed of sheets of neoplastic round cells (mast cells) on a preexisting dense collagenous stroma. Neoplastic cells have distinct cell borders, moderate amounts of amphophilic cytoplasm that often contain fine basophilic granules, a centrally located, round to oval nucleus with coarsely stippled chromatin and indistinct nucleolus. Anisocytosis and anisokaryosis are mild and there is 1 mitotic figure per 2.37 mm². There are multiple large, irregular, up to 5 mm diameter areas of lytic necrosis composed of brightly eosinophilic cellular and karyorrhectic debris, degenerate mast cells, and multifocal brightly eosinophilic, thick bands of collagen that are bordered by deeply basophilic fragmented mineral (collagen flame figures). Interspersed within the neoplastic sheets and collagenous tissue are macrophages containing intracytoplasmic brown globules (hemosiderin), few multinucleated giant cells (foreign body and Langhans type), and occassional eosinophils, foci of pale basophilic material (mucin), hemorrhage, fibrin, and edema. 

 

MORPHOLOGIC DIAGNOSIS:  Subcutis (per contributor): Mast cell tumor, Standardbred, equine

 

SLIDE D:

Signalment (JPC #4014162-02): 13 year old, spayed female domestic shorthair cat

 

HISTORY: Several cutaneous masses; this mass on the left shoulder

 

HISTOPATHOLOGIC DESCRIPTION (Slide D): Haired skin and subcutis: Expanding the dermis and subcutis, elevating the overlying epidermis, and separating adnexa is an unencapsulated, well-demarcated, densely cellular neoplasm composed of round cells (mast cells) arranged in sheets on a scant to moderate preexisting collagenous stroma. Neoplastic cells are separated from the overlying epidermis by a narrow zone of dermal collagen devoid of neoplastic cells (Grenz zone). Neoplastic cells have distinct cell borders, a scant to abundant amount of eosinophilic cytoplasm, and a centrally located, round to oval nucleus with coarsely clumped chromatin and 1-2 prominent nucleoli. Ansiocytosis and anisokaryosis are marked with frequent karyomegalic and pleomorphic cells and 1 mitotic figures per 2.37 mm².  Entrapped collagen fibers are brightly eosinophilic and hyalinized. There are multifocal dense perivascular lymphocytic infiltrates. 

 

MORPHOLOGIC DIAGNOSIS: Haired skin and subcutis: Mast cell tumor, mastocytic type, domestic shorthair, feline. 

 

SYNONYMS:  Mastocytoma, cutaneous mastocytosis

 

GENERAL DISCUSSION: 

• Note: This systemic focuses on cutaneous mast cell tumors; for information on primary gastrointestinal and oral mast cell tumors, see D-N04
• Dogs and cats (more common) can also develop systemic and visceral mastocytosis and MCT’s in the spleen 
• Cutaneous mast cell tumor (MCT):
  • Single or multiple nodular dermal proliferations of mast cells
  • Most common in dogs, but occur in other species
    • Dog: 15-21% of skin tumors are MCTs; the most frequent malignant or potentially malignant skin tumor; wide range of biologic behavior 
    • Cat: 12-20% of skin tumors are MCTs (second most common)
    • Horse: Growths similar to that in other species, but are called cutaneous mastocytosis rather than MCT
• Subcutaneous MCT:
  • Less common; possibly more favorable outcome (less aggressive), but data lacking and no validated grading system currently 

 

PATHOGENESIS:

• Proto-oncogene c-kit (C117, encodes for tyrosine kinase receptor “KIT protein”) and KIT ligand (mast cell growth factor) involved in MCT tumerogenesis; mutations in KIT or aberrant c-kit expression present in 15-40% of MCT’s
  • Internal tandem duplications (ITD) in the juxtamembrane domain result in constitutive activation of KIT; the most commonly detected c-KIT mutation is an ITD on exon 11 (45%), exon 8 (33%), and exon 9
  • Canine MCT with an activating point mutation in exon 11 have a poorer prognosis and are associated with higher histologic grades and proliferation markers than those without a c-kit mutation or with an exon 8 mutation
  • Canine MCT with mutations in exon 8 or exon 11 have increased therapeutic success with tyrosine kinase inhibitors 
• DNA mismatch repair (MMR) system (including repair proteins MSH2, MSH6, MLH1) is responsible for preserving genomic stability; when dysfunctional (mismatch repair deficiency [dMMR]), it has been linked to multiple neoplasms, including mast cell tumor (Inanaga, Vet Pathol 2021)
• Stem cell factor (SCF), a ligand of KIT, is expressed in 80% of feline MCT’s within mast cells on the margin of the tumor, but not near Ki67 positive tumor cells, indicating that SCF is an autocrine/paracrine mechanism involved in expansion of cutaneous MCTs, but not in tumor proliferation (Sakurai et al, J Comp Pathol 2018)
• Inflammation and erythema due to mast cell degranulation and release of inflammatory mediators (e.g. histamine, eosinophil/neutrophil chemotactic factors, prostaglandins, serine esterases, and TNF-a)
• Gastroduodenal ulceration occurs secondary to excessive histamine release, which causes local ischemia and stimulates H2 gastric parietal cells to increase acid secretion; occurs in 35-83% of cases of dogs with disseminated disease
• Massive synchronous degranulation may also result in hypotensive shock (rare) 

 

TYPICAL CLINICAL FINDINGS:

• Dogs: 
  • Average age 9 years old (range 3 weeks to 19 years); Boxer, bulldog, pug, retrievers, terriers, beagles, Shar Pei, and Schnauzers are predisposed; Shar Peis develop lesions at a younger age and are more likely to develop multiple lesions
  • All are considered potentially malignant; those in the inguinal area, perineum, scrotum, prepuce and digits have a worse prognosis; those on the eyelid do not metastasize 
• Horses: 
  • Usually adult males, but may occur in foals 
  • No reports of metastasis
• Cats:
  • Typically older cats (9-11 years), but young Siamese cats predisposed to multiple masses 

 

TYPICAL GROSS FINDINGS:

• Dog: 1-4cm irregular, nodular, rubbery to firm, erythematous, variably alopecic mass(es) on the skin, mouth, conjunctiva/eye lid, ear, or less often, inguinal area, perineum, scrotum, prepuce, and digits; often palpable similar to a lipoma
  • Poorly differentiated tumors grow rapidly, are less circumscribed, and often associated with inflammation and edema
  • With metastasis, may see lymphadenomegally, splenomegaly, splenic nodules, hepatomegaly, kidney nodules, epicardial nodules
  • A recent report showed widespread intrathoracic metastasis and neoplastic pericardial effusion in a French bulldog with high-grade cutaneous MCT (Yale et al, J Com Pathol 2020)
  • May develop gastroduodenal ulceration with disseminated disease 
• Cat: One to several firm, raised, pink, alopecic papules ranging from millimeters to several centimeters on the head, neck, or eyelid; less often may be a poorly defined swollen area; young Siamese cats more likely to have multiple masses 
• Horse: Solitary nodule on the head, trunk, neck, or limbs; may be hyperpigmented, alopecic or ulcerated 

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Dog
  • An unencapsulated, variably circumscribed dermal to subcutaneous neoplasm composed of diffuse loose sheets or densely packed cords, separating collagen bundles, of well- to poorly-differentiated round cells (mast cells) with abundant eosinophilic cytoplasm containing variable numbers of gray to blue fine metachromatic granules and central round nucleus; mitotic figures and pleomorphism vary
  • Mature eosinophils are often scattered diffusely among neoplastic cells
  • Grenz zone is typically present, separating the mast cells from an intact epidermis
  • +/- collagen flame figures: degenerate collagen with deposition of irregular, amorphous, sometimes radiating eosinophilic material  with an infiltrate of eosinophils
  • +/- ulceration, edema, tumor necrosis, eosinophilic or mononuclear leukocytic vasculitis, vascular necrosis, mineralization, mucinous extracellular matrix, collagen degeneration with secondary granulomatous inflammation
• Cat
  • Mastocytic type: unencapsulated dermal neoplasm with uniform, round to polygonal cells in sheets with cytoplasm that is clear, eosinophilic or faintly basophilic and round, central hyperchromatic nucleus (sometimes multinucleated); obvious granularity is infrequent (even with Giemsa or toluidine blue); often small clusters of lymphocytes and rare eosinophils scattered throughout neoplasm; collagen degeneration rare 
  • Histiocytic (atypical, histologic) type: usually multiple sequential tumors in the junction of the dermis and subcutis with mast cells that resemble histiocytes (may be mistaken for granulomatous inflammation); Giemsa and toluidine blue not helpful in highlighting granules; confirmation as MCT done via electron microscopy or immunohistochemistry 
• Horse
  • Generally similar to dogs histologically, but with prominent collagen degeneration, large aggregates of eosinophils and focal mineralization 
  • A recent case series in horses also described a “histiocytic-like atypical MCT” localized near the eyes (eyelid, conjunctiva) that were composed of large (up to 35um) round pleomorphic cells, large central nucleus, and abundant granular cytoplasm admixed with numerous eosinophils; these cells were confirmed to be mast cells with special stains and IHC (Elbahi et al, J Comp Pathol 2018)
• Grading Systems – aid in determining biologic behavior and prognosis
  • Dog (cutaneous only; conjunctival MCT correlates well); note that grading is only considered one prognostic factor and should be used in conjunction with clinical picture (age, clinical progression, site, stage, completeness of surgical margins) and other prognostic markers (e.g. proliferation markers, KIT expression, c-KIT mutation)
    •    Kiupel grading system (2 tier) – more commonly used due to more objectivity in its criteria; low or high grade based mitotic count and nuclear/cellular morphology
      • Low grade: does not possess any of the features of malignancy listed below; MST >2 years; rarely metastasizes 
      • High grade: possesses any of the following features: 7+ mitotic figures per 10 consecutive HPF’s, 3+ multinucleated cells with 3+ nuclei, 3+ bizarre nuclei in 10 HPF, karyomegally in at least 10% of the neoplastic cells (variation by at least 2-fold); MST <4 months
    •    Patnaik grading system (3 tier) – not widely used anymore due to subjectivity and variability in grading; grade I, II, or III based on the extent of tissue involvement, cellularity, nuclear/cellular morphology, granularity, mitoses, and stromal reaction (hyalinization, necrosis, and hemorrhage)
      • Grade I: well differentiated cells, confined to dermis, no mitoses or necrosis; excellent long-term prognosis
      • Grade II: moderately to highly cellular, extends into lower dermis or subcutis, 0-2 mitotic figures per HPF, stromal reaction present; difficult to predict behavior (majority benign, but around 20% are aggressive)
      • Grade III: densely cellular, pleomorphic cells with vesicular nuclei and prominent nucleoli, 3-6 mitotic figures per HPF, subcutaneous involvement, stromal reaction present; guarded to poor prognosis (high recurrence and metastatic rate) 
    •    These grading systems can be combined, creating 4 categories with different prognoses (the recommended method per OPWG Canine Cutaneous Mast Cell Tumor Subgroup on Grading, Berlato et al, Vet Pathol 2021) 
      • Grade I/low grade: excellent prognosis with no MCT related deaths and low risk of lymph node (6%) and distant (2%) metastasis
      • Grade I/low grade: good prognosis with 3-17% rate of MCT related deaths and moderate risk of lymph node (16%) and distant (2%) metastasis; MST >96 months
      • Grade II/high grade: fair to guarded prognosis with 14-56% of MCT related deaths and moderate risk of lymph node (15%) and distant (2%) metastasis: MST 7.5-23.3 months
      • Grade III/high grade: guarded to poor prognosis with 67-75% MCT related deaths and high risk of lymph node (46%) and distant (21%) metastasis; MST 3.6-6.8 months
    •    Note that mitotic count is a distinct indicator of clinical behavior and considered an independent prognostic indicator; a mitotic count >5 corresponded with a MST of 2-5 months and is significantly associated with metastatic rate (but not recurrence rate); however, the mitotic count is highly variable within sections of MCT and the use of computerized calcuations may be helpful in identifying areas with the highest rates (Bertram et al, Vet Pathol 2020)
    •    Sterology is highly accurate and can be used to help remove inter- and intraobserver variability when assessing nuclear pleomorphism (Casanova, Vet Pathol 2021)
  • Cat
    •    No widely accepted grading system due to needing validation on various feline MCT subtypes 
    •    A 2-tier system has been proposed, either low or high grade, based on tumor diameter, anisocytosis, hyperchromasia, nuclear pleomorphism, and mitotic count (>5 has poor MST)
      • High grade is classified as a mitotic count of >5, plus two of the three findings: tumor diameter >1.5cm, nuclear pleomorphism (irregular shape), and nucleolar prominence/chromatin clusters in >50% of mast cells
      • High grade associated with significantly reduced survival times (MST 349 days); rate of metastasis low (5%) and recurrence common (25-50%)
• Margins
  • General rule: 2-3cm laterally and one tissue plane in depth needed to minimize recurrence; low grade tumors likely do not need wide margins (only 4% recurrence with margins of <3mm), but 36% of high grade tumors recur locally with wide margins
• Metastasis
  • In dogs, >80% of high grade MCT will metastasize (regional lymph node [most common], spleen, liver, kidney, heart, lungs, bone marrow [rare])
  • Touldine blue is particularly helpful in highlighting lymph node metastasis, but it must be kept in mind that lymph nodes will normally have low numbers of mast cells present in them and not all lymph nodes with metastasis will be grossly enlarged (Sabattini, Vet Pathol 2022)
  • Bisecting a lymph node at the hilum (directly in the middle) is reliable for detection of metastasis, although additional step-sections will increase accuracy (Sabattini, Vet Pathol 2022)

 

ULTRASTRUCTURAL FINDINGS:

• Resemble normal mast cells
• Cytoplasm contains many membrane bound granules, which appear as single or fused vesicles that lack microvilli; fine fibrillar material forms a loose network within these vesicles

 

ADDITIONAL DIAGNOSTIC TESTS:

• Cytology: 
  • Individualized, round cells with variable numbers of purple cytoplasmic granules (may not stain well with Diff-Quik; stain well with May-Grunwald-Giemsa or Wright’s stain, but may cause granules to obscure the nuclear features); the background often contains granules from ruptured cells or degranulation, variable numbers of eosinophils (sometimes out-numbering the mast cells), fibroblasts (reactive fibroplasia), collagen strands (collagenolysis)
  • Grading requires further investigation, but few systems exist (see below); limitations include inability to differentiate between cutaneous and subcutaneous MCT, the variability in staining preparations, and discrepancies between cytologic and histologic schemes (e.g. binucleation is considered in cytologic grading while it is not in histologic grading):
  • Camus 2-tier grading system:
    • Considered high grade if poorly granulated or there are at least two of the following features: presence of mitotic figures, nuclear pleomorphism (“non-circular”), binucleation or multinucleation and anisokarysosis (>50% difference) 
    • This grading scheme is predictive for survival time, but may overestimate high-grade cases 
  • Kiupel style 2-tier grading system: 
    • Similar to Camus system, but does not assess granulation 
  • Patnaik stype 3-tier grading system: 
    • Grade I (well differentiated): numerous, distinct granules with uniform nuclei
    • Grade II (intermediate): fewer granules, nuclei may vary in shape and size
    • Grade III (poorly differentiated): few or no cytoplasmic granules, nuclei have marked atypia (anisokaryosis, coarse chromatin, multiple prominent nucleoli) with mitotic figures and multinucleated cells 
  • Using stereologic tools (2D-nucleator method) or morphometry (image analysis) can assist with prognostication (i.e. assessing nuclear areas) and are highly accurate (Marcos, J Vet Diagn Invest 2022)
• Histochemistry to highlight metachromatic granules (absence of granules does not exclude a MCT): Giemsa, toluidine blue, astral blue, Perls’ Prussian blue, luna
• Electron microscopy: can confirm presence of mast cell granules that are otherwise unable to be visualized with histochemistry (e.g. feline MCT’s)
• Immunohistochemistry for mast cells (neoplastic or normal): 
  • c-KIT (CD117) positive (most commonly used) 
    • Note that c-KIT is also expressed on some hematopoietic stem cells, gastrointestinal interstitial cells of Cajal, melanocytes, and others 
  • Carboxypeptidase A3 (CPA3) positive (Hamalainen, Vet Pathol 2022)
  • Trypase or chymase positive (Hamalainen, Vet Pathol 2022): ezymes within mast cell granules that can be used to identify mast cells and their subpopulations; connective tissue mast cells (the primary type in the body) contain both; [gastrointestinal] mucosal mast cells only contain tryptase 
• Prognostic tests:
  • Ki-67, AgNOR (agryrophilic nuclear organizing region), proliferating cell nuclear antigen (PCNA), mitotic count: high proliferation indices are associated with a worse prognosis and shorter MST; higher Ki-67 is associated with MCT size and age of the patient (Firsching, J Comp Pathol, 2022); mitotic count is most accurate when using computer assisted algorithms (Bertram, Vet Pathol, 2022)
  • c-KIT (CD117) PCR: mutations in c-KIT have a worse prognosis (especially exon 11); expression patterns also have prognostic significance (pattern I – perimembrane, pattern II – focal or stippled cytoplasmic staining, pattern III – diffuse cytoplasmic staining) with increased cytoplasmic staining have a poorer prognosis
  • Beclin-1 immunohistochemistry: Beclin-1 is an autophagy protein; while not prognostic, it is predictive for MST after adjunctive treatment; dogs with high beclin-1 expression had poorer survival times (Knight, Vet Pathol 2022)
  • NANOG, a pluripotency factor, does not correlate with proliferative activity and is not a reliable prognostic factor (Joselevitch et al, Vet Pathol 2018)
• Hematology
  • Mastocytemia (mast cells in the blood) highly suggestive of disseminated mast cell neoplasia (systemic mastocytosis), but does not necessarily indicate myeloid neoplasia or leukemia 
  • In dogs, mastocytemia was more common in those without MCT (indicating a reactive process) 

 

DIFFERENTIAL DIAGNOSIS:

• Accumulations of mast cells
  • Abundant mast cells may be seen with parasitic, mycotic, allergic, and idiopathic inflammatory syndromes, but these will not have sheets of mast cells
  • Urticaria pigmentosa: diffuse, dermal and subcutaneous infiltrates of well differentiated mast cells over large areas of the body in cats, dogs, and foals 
  • Mast cell hyperplasia: Multiple, spontaneously regressing aggregates of mast cells in young dogs, cats, pigs, calves, and foals
• Other round cell neoplasms (for poorly granular mast cell tumors):

• Lymphoma
• Plasmacytoma
• Histiocytoma
• Transmissible venereal tumor

• Horse (for eosinophilic/mastocytic inflammation):

• Cutaneous habronemiasis
• Cutaneous onchocerciasis 
• Eosinophilic granuloma 

 

COMPARATIVE PATHOLOGY:

• Ferrets: Similar in morphology and behavior to well-differentiated feline MCTs
• Cattle: Rare (more common to have visceral MCT that metastasizes to the skin); usually multiple cutaneous masses with associated with visceral mast cell aggregates; morphologically well-differentiated; congenital cutaneous MCT has been reported with well-circumscribed 1-7cm nodules all over the body
• Swine: Mast cell nodules have been described as tumors and as inflammatory aggregates, perhaps in response to Eperythrozoon; may be single or multiple masses with similar morphology to well-differentiated feline MCTs; visceral mast cell aggregates found in animals with multiple cutaneous masses; metastasis rare; intracytoplasmic granules often faint and need toluidine blue to visualize; KIT is a promising diagnostic marker (Rasche, J Vet Diagn Invest, 2022) 
• Reptiles: MCT has been rarely reported in lizards, turtles, and snakes 
• Non-human primate: MCT has been rarely reported
• Avians: Reported in chickens, owls, and rarely psittacines; special stains may be needed to highlight the granules
• Malayan Tiger: developed cutaneous and splenic mastocytosis at 1 week old; started as well-circumscribed, erythematous lesions on the face, torso, and paws which either regressed (face, torso) by 1 year old or developed into pendulous masses up to 6.5cm (paws) which were removed without recurrence; somatic mutation in exon 8 of c-KIT (Smedley, J Vet Diagn Invest, 2022)
• Goats: sheets of large round cells with finely vacuolated cytoplasm that lacks visible granules with frequent interspersed eosinophils; often no granules visible with metachromatic stains, but will be positive for CD117 immunolabeling (O’Neill, Vet Pathol 2021)

 

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