JPC SYSTEMIC PATHOLOGY

DIGESTIVE SYSTEM

October 2024

D-N04

 

SLIDE A: Signalment (JPC #1800099): Adult cat

 

HISTORY: None

HISTOPATHOLOGIC DESCRIPTION: Small intestine: Focally and markedly expanding the tunica muscularis, submucosa, and lamina propria, is an 8 x 4 mm, unencapsulated, well-demarcated, infiltrative neoplasm composed of round cells arranged in sheets and vague cords on a preexisting fibrovascular stroma and infiltrating between smooth muscle cells. Neoplastic cells have variably distinct cell borders, a moderate amount of pale, eosinophilic, finely granular cytoplasm, and a round to oval, centrally located nucleus with finely-stippled chromatin and 1-5 variably distinct nucleoli. Anisocytosis and anisokaryosis are mild, and the mitotic count averages 6 per 2.37mm². Neoplastic cells are admixed with low numbers of eosinophils and rare lymphocytes and plasma cells. Within the tunica muscularis, neoplastic mast cells surround and separate myocytes. Neoplastic mast cells expand the lamina propria up to 1.2 mm in width, surrounding and separating crypts that are often elongated, tortuous, lined by cells with enlarged vesiculate nuclei that are often piling up, and contain mitotic figures within the more superficial mucosa (crypt hyperplasia). There is a focally extensive area of acute hemorrhage, fibrin, and edema within the inner circular layer of the tunica muscularis adjacent to neoplastic cells. 

 

Slide B (Giemsa): Multifocally, neoplastic cells contain metachromatic cytoplasmic granules.

MORPHOLOGIC DIAGNOSIS: Small intestine: Mast cell tumor, breed not specified, feline

 

GENERAL DISCUSSION:

• Note: This systemic focuses on primary gastrointestinal mast cell tumors (MCT) and briefly on oral mast cell tumors; for information on cutaneous/subcutaneous MCT, see I-N21
• Mast cell leukemia is rare
• MCTs is common neoplasm in spleen of cats; can have mastocytosis (disseminated mast cell neoplasia)
• Mastocytemia is highly suggestive but not indicative of systemic mastocytosis 
  1. Mastocytemia may be reactive or neoplastic
• Mucosal mast cells normally make up 2-3% of the cell population in the lamina propria and differ from the rest of the body’s mast cells both histochemically and physiologically. 
  1. Small cells, lack membrane bound IgE, and release proinflammatory mediators through paracrine cytokines
  2. Contain tryptase (like CTMC’s), but not chymase; less histamine 
  3. Granules are few and poorly staining with formalin fixation due to their granules containing predominantly chondroitin sulfates and glycosaminoglyans rather than heparin; stain well if tissue is fixed with basic lead acetate or Carnoy’s fluid; granules are variably electron-dense on EM
  4.  Play a role in epithelial integrity, blood flow control, coagulation, smooth muscle contraction, stimulation of enteric nervous system, peristalsis, and antibody-dependent recognition of parasites and microorganism. 
• Primary Gastrointestinal MCT 
  • Uncommon; most frequently seen in aged dogs and rarely cats; most common in stomach and least common in colon
  • Comprised predominantly of mucosal mast cells
  • Can resemble other invasive round cell tumors (carcinoids, lymphomas, and gastrointestinal stromal tumors) on biopsy; therefore, definitive diagnosis requires histochemical and possibly immunohistochemical investigation
  • Metastasis occurs most often to mesenteric lymph nodes, followed by liver, spleen, and rarely the lungs
• Oral MCT
  • Uncommon (5% of oral masses); most frequently in middle aged dogs and cats; most common on lip, but also seen in submucosa of the tongue, gums, and hard palate
  • Use similar criteria for diagnosis as cutaneous MCT, but are more likely to be malignant, have lymph node metastasis, and poorer prognosis 
  • Should be considered a differential for oral lesions resembling granulation tissue or eosinophilic granuloma

PATHOGENESIS:

• There are two major types of mast cells; differ histochemically and physiologically:
  • Connective tissue mast cells (CTMC’s): 
    • Wide-spread distribution, including non-mucosal layers of GI tract
    • Classic mast cells; granules stain well due to abundance of heparin 
  • Mucosal mast cells (MMC’s):
    • Normally make up 2-3% of the cells in the lamina propria of the GI tract 
    • Small cells; granules are few and poorly staining with formalin fixation due to their granules containing predominantly chondroitin sulfates and glycosaminoglyans rather than heparin; granules are variably electron-dense on EM
    • Contain tryptase (like CTMC’s), but not chymase; less histamine 
    • Lack membrane-bound immunoglobulin E (IgE) and release proinflammatory mediators through paracrine cytokines 
  • Globule leukocytes (GL’s) or interepithelial mucosal mast cell (ieMMC):
    • Reported in the intestinal, respiratory, and urogenital systems; found in the epithelium of crypts/lower villi and lamina propria 
    • Poorly understood; possibly a third type of mast cell or, rather, may originate from mast cells or large granular lymphocytes 
    • Mononuclear cell with large eosinophilic cytoplasmic granules; associated with parasitism 
• Proliferation of intestinal mast cells (MMC’s and GL’s) is T-cell dependent 

TYPICAL CLINICAL FINDINGS:

• Primary GI MCT: Vomiting, diarrhea, melena; usually no eosinophilia or circulating mast cells in the blood
• Oral MCT: Nodule in mouth that resemble granulation tissue or eosinophilic granuloma.

TYPICAL GROSS FINDINGS:

• Tan-colored, firm, thickened area in GI tract; up to several cm in size
• GI ulceration not a common feature mucosal mast cell tumors of intestinal origin due to less histamine release, expect as a result of mucosal effacement by the tumor
• +/- enlarged regional lymph nodes

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Tissue architecture effaced by granular round cells accompanied by variable number of eosinophils; typically arranged in infiltrative cords, but occasionally form endocrine-like packets surrounded by delicate fibrovascular stroma
  1. Wide pleomorphic, variable appearance
  2. Range from mature cells with abundant cytoplasmic granules to anaplastic and pleomorphic round or spindle shaped cells, sometimes with giant syncytia +/- discernible granules
  3. Those with abundant metachromatic granules must be differentiated from connective tissue mast cell tumors metastatic to the GI
  4. Eosinophil presence is not definitive for MCT as eosinophils are common in some intestinal lymphomas and are a normal cell type in the lamina propria. 
  5. In cats, there is a subset of GI MCT that has significant collagen stroma.
  6. MCT within body cavities may cause effusions, exfoliating large number of mast cells into the effusion; cells may have “packeted” granules leading to the nucleus to be poorly stained or not at all

 

ULTRASTRUCTURAL FINDINGS:

• Cytoplasm contains many membrane bound granules that appear as single or fused vesicles; fine fibrillar material forms a loose network within these vesicles
• Few tumor cells contain electron-dense fibrillar granules or intermediate forms
• Crystalline electron-dense granules that are present in CTMC’s are rarely evident 

 

ADDITIONAL DIAGNOSTIC TESTS:

• Metachromatic histochemical stains highlight metachromatic granules: Acid toluidine blue, Alcian blue, Giemsa, Luna mast
  • Absence of granules does not exclude a MCT
• Immunohistochemistry
  • c-KIT (CD117) and mast cell tryptase positive; however:
    • Tryptase is not always detectable 
    • Only 33% of feline MCTs are c-KIT positive
    • Gastrointestinal stromal tumors are also c-KIT positive, but they lack metachromatic granules 
  • CD3 negative (distinguishing from T-cell lymphomas)
  • Cytokeratin negative (distinguishing from carcinomas)
  • Chromogranin and synaptophysin negative (distinguishing from carcinoids)

 

DIFFERENTIAL DIAGNOSES:

• Oral MCT:
  • Eosinophilic granuloma:
  • Granulation tissue 
• Intestinal MCT:
  • Metastatic cutaneous mast cell tumor 
  • Lymphoma: Most common intestinal neoplasia in cats; usually monomorphic population of lymphocytes; may have eosinophilic infiltrates 
  • Large granular lymphoma (LGL): Cats; T cells or NK cells; large, red, cytoplasmic granules; often mixed with other inflammatory cells 
  • Intestinal neuroendocrine carcinoma (carcinoid): Arise from neuroendocrine cells; arranged in nests and packets; dense, round-to-oval, membrane bound secretory granules on EM
  • Gastrointestinal stromal tumors: Spindle cells arranged in interlacing fascicles or storiform pattern; C-KIT positive, lack of metachromatic granules with toluidine blue
  • Tumors of globule leukocytes: Cats; round, uniform cells with fewer and larger eosinophilic granules 
  • Adenocarcinoma: Usually form tubules with mucin production
  • Eosinophilic inflammatory bowel disease: Usually high numbers of tissue, bone marrow, and blood eosinophils; characteristic eosinophil granules on EM
  • Feline gastrointestinal eosinophilic sclerosing fibroplasia (FGESF, see D-M19): Ulcerated, intramural mass usually in stomach/pyloric sphincter with specific pattern of fibrosis/sclerosis and which may efface adjacent lymph nodes

 

COMPARATIVE PATHOLOGY:

• Intestinal mast cell tumors are rare in other species: Reported in snakes
• Cutaneous/Subcutaneous MCT’s (I-N21)

 

REFERENCES:

1. Ackermann MR. Inflammation and Healing. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:119, 153.
2. Brannick EM, Newkirk KM, Schaefer MW. Neoplasia and Tumor Biology. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:383-384. 
3. Durham AC, Boes KM. Bone Marrow, Blood Cells, and the Lymphoid/Lymphatic System. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:840-841.
4. Fisher DJ. Cutaneous and Subcutaneous Lesions. In: Valenciano AC, Cowell RL, eds. Diagnostic Cytology and Hematology of the Dog and Cat. 5th ed. St. Louis, MO: Elsevier Mosby; 2014:88. 
5. Haddad JL, Marks Stowe DA, Neel JA. The Gastrointestinal Tract. In: Valenciano AC, Cowell RL, eds. Diagnostic Cytology and Hematology of the Dog and Cat. 5th ed. St. Louis, MO: Elsevier Mosby; 2014:312. 
6. Ossiboff RJ. Serpentes. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. London, UK: Academic Press; 2018:898. 
7. Peters LM, Meyer DJ. Chapter 9: Hepatobiliary System. In: Raskin RE, Meyer DJ, & Boes KM eds. Canine and Feline Cytopathology: A Color Atlas and Interpretation Guide. 4th ed. St. Louis, MO: Elsevier; 2022:351.
8. Raskin RE, Conrado FO. Chapter 3: Integumentary System. In: Raskin RE, Meyer DJ, & Boes KM eds. Canine and Feline Cytopathology: A Color Atlas and Interpretation Guide. 4th ed. St. Louis, MO: Elsevier; 2022:88-90.
9. Spagnoli ST, Gelberg HB. Alimentary System and the Peritoneum, Omentum, Mesentery, and Peritoneal Cavity. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:403. 
10. Uzal FA, Plattner BL, Hostetter JM. Alimentary System. In: Maxie MG, ed. Jubb, Kennedy & Palmer's Pathology of Domestic Animals. Vol 3. 6th ed. St. Louis, MO: Elsevier; 2016:27, 64, 109. 
11. Valenciano AC, Rizzi TE. Abdominal, Thoracic, and Pericardial Effusions. In: Valenciano AC, Cowell RL, eds. Diagnostic Cytology and Hematology of the Dog and Cat. 5th ed. St. Louis, MO: Elsevier Mosby; 2014:2333-234, 243.

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