JPC SYSTEMIC PATHOLOGY
DIGESTIVE SYSTEM
September 2021
D-N06

Signalment: (JPC #2300082): 13-year-old female shepherd mix dog

 

HISTORY: None

 

HISTOPATHOLOGIC DIAGNOSIS: Anal sac: Infiltrating the connective tissue surrounding the anal sac epithelium, effacing approximately 30% of anal sac apocrine glands, and compressing and infiltrating adjacent skeletal muscle is a well demarcated, unencapsulated, multilobulated, densely cellular neoplasm composed of cuboidal to columnar polygonal cells arranged in cords, tubules, acini, and solidly cellular areas separated and supported by a fine fibrovascular stroma. Multifocally, neoplastic cells palisade around a central lumen that is either clear or filled with eosinophilic material (rosettes), or palisade around small caliber blood vessels (pseudorosettes), and tubuloacinar lumina occasionally contain eosinophilic amorphous material (secretory product). Neoplastic cells have variably distinct cell borders and a moderate amount of eosinophilic granular cytoplasm. Nuclei are often basilar and are round to oval with coarsely stippled chromatin and up to two nucleoli. There is mild anisokaryosis, minimal anisocytosis, and rare single cell death/necrosis. Mitoses average 2 per HPF (20 per 2.37 mm²) with occasional bizarre mitoses. Multifocally at the periphery of the neoplasm, there are clusters of neoplastic cells within lymphatics and blood vessels. There is multifocal mild hemorrhage and scattered lymphocytes, plasma cells, and hemosiderin-laden macrophages within the connective tissue stroma. Multifocally, similar inflammatory cells infiltrate the subepithelial connective tissue of the anal sac, and remaining anal sac apocrine glands are moderately ectatic and lined by attenuated epithelium.

 

MORPHOLOGIC DIAGNOSIS: Anal sac: Anal sac gland adenocarcinoma, shepherd mix, canine.

 

SYNONYMS: Anal sac gland carcinoma, adenocarcinoma of the apocrine glands of the anal sac

 

GENERAL DISCUSSION:

• Most common malignant perianal neoplasm of dogs with higher incidence in old intact females and neutered males; rare in cats
• Arises from the apocrine secretory epithelium found in the walls of anal sac
• Highly malignant: Commonly metastasize to iliac and sublumbar lymph nodes and occasionally to lung, liver, bone, and spleen
• The majority of dogs with anal sac gland adenocarcinomas have humoral hypercalcemia of malignancy
• Some populations of anal sac gland carcinomas may be neuroendocrine in nature; there is no relationship between neuroendocrine differentiation and clinical outcome (clinical outcome is more related to the histological pattern)

 

PATHOGENESIS (for hypercalcemia):

• Neoplastic cells produce parathyroid hormone-related protein (PTHrP) which results in paraneoplastic hypercalcemia in 25-90% of cases which is associated with shorter survival time
• Normal adult tissues produce PTHrP in miniscule amounts; it has an unknown paracrine or autocrine effect
• In fetal tissues, PTHrP functions in calcium transport across the placenta, cell growth, and differentiation
• PTHrP is nearly identical in biological activity to parathyroid hormone
• PTHrP uses three primary mechanisms which induce hypercalcemia
  • Stimulation of osteoclastic bone resorption
  • Increase in calcium reabsorption in the distal convoluted tubules
  • Activation of vitamin D precursors, resulting in increased intestinal absorption of calcium
• Hypercalcemia normalizes following complete surgical excision

 

TYPICAL CLINICAL FINDINGS:

• Primarily due to hypercalcemia: polyuria/polydipsia, bradycardia, paresis, lethargy
• Tenesmus, constipation, perianal pruritus
• Hypophosphatemia
• Serum PTH lower than normal
• Survival time after surgery is significantly associated with presence of sublumbar lymphadenopathy and sublumbar lymph node extirpation

 

TYPICAL GROSS FINDINGS:

• Perianal mass, ventrolateral to the anus; usually unilateral and not attached to the skin (overlying epidermis is mobile and rarely ulcerates)
• Tan, lobulated, with multiple cysts on cut surface
• Can be occult, growing cranially within the pelvic canal with no outward visible mass; often an incidental finding on physical exam
• May invade rectum or anus

 

TYPICAL CYTOLOGY FINDINGS:

• Highly cellular, composed of loosely cohesive cell clusters and many free, intact nuclei with poorly defined cell borders (naked nuclei)
• Acinar and/or rosette forms may be visible, may form papillary shapes
• When cell borders are distinguishable, high nuclear:cytoplasmic ratio
• Anisocytosis is difficult to judge (due to naked nuclei), anisokaryosis and cellular pleomorphism are typically mild despite malignant nature, although may occasionally have a high rate of cellular and nuclear pleomorphism

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Forms glandular acini with projections of apical cytoplasm extending into lumen
• Three patterns (one or more patterns can be seen in a single tumor):
  • Solid type: Sheets of tumor cells, fine fibrovascular stroma
  • Rosette type: Rosette formation with basilar nuclei
  • Tubular type: Multiple tubular lumina containing eosinophilic secretions
• Variable amounts of eosinophilic cytoplasm
• May exhibit decapitation excretion
• Bland monomorphic population despite the malignant behavior
• Histologically distinct from more common perianal (circumanal/hepatoid) gland

 

ULTRASTRUCTURAL FINDINGS:

• Numerous profiles of rough ER
• Well developed Golgi apparatus
• Electron dense granules
• Large lysosome like dense bodies
• Clusters of free ribosomes

 

ADDITIONAL DIAGNOSTIC TESTS:

• IHC: CK7+/CK14-; most are immunopositive for Bcl-2
  • This is a unique pattern among canine cutaneous epithelial neoplasms
• IHC: Neoplastic cells are weakly immunopositive for PTHrP, chromogranin A, and neuron-specific enolase

 

DIFFERENTIAL DIAGNOSIS:

Perianal neoplasia:

• Clitoral gland carcinoma: Overlapping features on cytology and histology
• Anal sac gland adenoma: Little mitotic activity; well encapsulated; rare
• Perianal (circumanal/hepatoid) gland neoplasms:
  • Hepatoid gland adenoma: Common in old intact male dogs; well organized trabeculae of polygonal cells with abundant granular cytoplasm and a peripheral rim of reserve cells; little atypia
  • Hepatoid gland epithelioma: Predominance of basaloid cells with mitoses but little atypia
  • Hepatoid gland carcinoma: Disorganized, pleomorphic basaloid cells and hepatoid cells with mitotic activity in both; invasive growth
• Sebaceous and apocrine tumors
• Squamous cell carcinoma of the anal sac

 

Hypercalcemia

Hyperparathyroidism (primary: idiopathic or functional parathyroid neoplasms)

Addison's & Acidosis

Renal Disease (horses, rarely in young dogs)

Vitamin D toxicosis: Hypervitaminosis D, Calciferol rodenticides, Vit D glycoside plants (Solanum malacoxylon, Cestrum diurnum, Trisetum flavescens)

Immobilization

Osteolytic lesions

Neoplasia (5: apocrine gland adenocarcinoma of anal sac, lymphoma, multiple myeloma, metastatic bone tumors, SCC in horse)

Spurious (granulomatous disease, hyperproteinemia, hemoconcentration, thiazide diuretics)

 

 

COMPARATIVE PATHOLOGY:

• HHM has also been reported in cats and horses
• Canine anal sac gland carcinoma is used in nude mice models for the study

of human HHM

 

REFERENCES:

1. Fisher DJ. Cutaneous and Subcutaneous Lesions.  In: Valenciano AC, Cowell RL, eds. Cowell and Tyler’s Diagnostic Cytology and Hematology of the Dog and Cat. 5^th St. Louis, MO: Elsevier; 2020:95.
2. Goldschmidt MH, Goldschmidt KH. Epithelial and Melanocytic Tumors of the Skin. In: Meuten J, ed. Tumors in Domestic Animals. 5th ed. Ames, Iowa: Iowa State Press; 2017:120-122.
3. Goldschmidt MH, Munday JS, Scruggs JL, Klopfleisch R, Kiupel M. Volume 1: Epithelial Tumors of the Skin. In: Kiupel M, ed. Surgical Pathology of Tumors of Domestic Animals. Washington, DC, Davis-Thompson DVM Foundation; 2019: 179-184.
4. Latimer KS. Duncan and Prasse’s Veterinary Laboratory Medicine: Clinical Pathology. 5th ed. Ames, Iowa: Iowa State University Press; 2011:299-304.
5. Mauldin EA, Peters-Kennedy J. Integumentary System. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 3. 6th ed. St Louis, MO: Elsevier; 2016: 720.
6. Miller MA. Endocrine System. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease, 6th ed. St. Louis, MO: Elsevier; 2017:719.
7. Ogawa B, Taniai E, Hayashi H, et al. Neuroendocrine carcinoma of the apocrine glands of the anal sac in a dog. J Vet Diagn Invest. 2011;23(4):852.
8. Pieper JB, Stern AW, LeClerc SM, Campbell KL. Coordinate expression of cytokeratins 7 and 14, vimentin, and Bcl-2 in canine cutaneous epithelial tumors and cysts. J Vet Diagn Invest. 2015;27(4):497-503.
9. Pontana CP, Padgett S, Gamblin RM. Surgical excision of anal sac apocrine gland adenocarcinomas with and without adjunctive chemotherapy in dogs: 42 cases (2005-2011). J Am Vet Med Asso. 15;246(8):877-84.
10. Raskin RE. Skin and subcutaneous tissues. In: Raskin RE, Meyer DJ, eds. Canine and Feline Cytology: A color atlas and interpretation guide, 3^rd St. Louis, MO:Elsevier. 2016:34-90.
11. Rosol TJ, Grone A. Endocrine Glands. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 3. 6th ed. St Louis, MO: Elsevier; 2016: 274, 307-308.
12. Rosol TJ, Meuton DJ. In: Meuten J, ed. Tumors in Domestic Animals. 5th ed. Ames, Iowa: Iowa State Press; 2017:816-820.
13. Suzuki K, Morita R, Hojo Y et al. Immunohistochemical characterization of neuroendocrine differentiation of canine anal sac glandular tumors. J Comp Pathol. 2013;149(2-3):199.
14. Verin R, Cian F, Stewart J, et al. Canine clitoral carcinoma: a clinical, cytologic, histopathologic, immunohistochemical and ultrastructural study. Vet Pathol. 2018;55(4):501-509.

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