JPC SYSTEMIC PATHOLOGY
DIGESTIVE SYSTEM
September 2018
D-N06

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

HISTORY:  None

HISTOPATHOLOGIC DIAGNOSIS:  Anal sac:  Infiltrating the connective tissue underlying the anal sac epithelium, and effacing and replacing adjacent anal sac glands and skeletal muscle, is an unencapsulated, multilobulated, densely cellular neoplasm composed of 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, which is either clear or filled with eosinophilic material, forming rosette-like structures.  Neoplastic cells are polygonal to columnar with variably distinct cell borders and a moderate amount of eosinophilic granular cytoplasm.  Nuclei are often basilar and round to oval with coarsely stippled chromatin, and up to two nucleoli.  There is mild anisokaryosis.  Mitoses average 2 per HPF with occasional bizarre mitoses.  Multifocally at the periphery of the neoplasm, there are clusters of neoplastic cells within lymphatics and blood vessels.  There is rare scattered single cell necrosis, occasional eosinophilic amorphous material (secretory product) in tubuloacinar lumina, multifocal mild hemorrhage and scattered lymphocytes, plasma cells, and hemosiderin-laden macrophages which occasionally surround clear acicular cholesterol clefts within the connective tissue stroma.  Multifocally, similar inflammatory cells infiltrate the subepithelial connective tissue of the anal sac, and remaining apocrine glands are moderately ectatic with attenuated epithelium.

MORPHOLOGIC DIAGNOSIS:  Anal sac:  Anal sac gland adenocarcinoma (adenocarcinoma of the apocrine glands of the anal sac), shepherd mix, canine.

GENERAL DISCUSSION:

• Most frequent cause of Humeral Hypercalcemia of Malignancy
• Most common malignant perineal neoplasm of dogs with higher incidence in old intact females and neutered males; rare in cats
• Arises from the apocrine secretory epithelium found on the walls of anal sac
• Highly malignant: Commonly metastasize to iliac and sublumbar lymph nodes and occasionally to lung, liver, bone and spleen
• 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
• 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):

• 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
• Tenesmus, constipation, perineal pruritus
• Hypercalcemia: PU/PD, bradycardia, paresis, lethargy
• Hypophosphatemia
• Serum PTH lower than normal
• Survival time after surgery is significantly associated with presence of sublumbar lymhadenopathy and sublumbar lymph node extirpation

TYPICAL GROSS FINDINGS:

• Perineal mass, ventrolateral to the anus; usually unilateral and not attached to the skin
• 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
• Overlying epidermis is mobile and rarely ulcerates with invasion of rectum or anus

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Forms glandular acini with projections of apical cytoplasm extending into lumen
• Histologically distinct from more common perianal (circumanal) gland
• Three patterns:  One or more pattern 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
• Neoplastic cells are weakly positive for PTHrP, chromogranin A, neuron-specific enolase immunohistochemical stains

ULTRASTRUCTURAL FINDINGS:

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

DIFFERENTIAL DIAGNOSIS:

• Perianal neoplasia
• Anal sac gland adenoma:  Little mitotic activity; well encapsulated; rare
• Hepatoid gland adenoma:  Common in old intact male dogs; well organized trabeculae of polygonal cells with abundant granular cytoplasm and peripheral reserve cells; little atypia
• Hepatoid gland epithelioma:  Basaloid cells w/ mitoses but little atypia
• Hepatoid gland carcinoma:  Pleomorphic basaloid cells and hepatoid cells with mitotic activity; invasive growth
• Sebaceous and apocrine tumors
• Squamous cell carcinoma of the anal sac

Hypercalcemia

Hyperparathyroidism (primary: idiopathic or functional parathyroid neoplasms)

Addisons & 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 dz, hyperproteinemia, hemoconcentration, thiazide diuretics)

COMPARATIVE PATHOLOGY:

• HHM has also been reported in cats and horses
• Anal sac gland carcinoma in dogs is used in nude mice models for the study of human HHM

References:

1. 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.
2. Latimer KS. Duncan and Prasse’s Veterinary Laboratory Medicine: Clinical pathology. 5th ed. Ames, Iowa: Iowa State University Press; 2011:299-304.
3. 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.
4. Miller MA. Endocrine System. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2017:719.
5. 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.
6. Pontana CP, Padgett S, Gamblin RM. Surgical excision of anal sac apocrine gland adenocarcinomas with and without adjuctive chemotherapy in dogs: 42 cases (2005-2011). J Am Vet Med Asso. 2015 Apr 15;246(8):877-84.
7. 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.
8. Rosol TJ, Meuton DJ. In: Meuten J, ed. Tumors in Domestic Animals. 5th ed. Ames, Iowa: Iowa State Press; 2017:816-820.
9. Suzuki K, Morita R, Hojo Y et al. Immunohistochemical characterization of neuroendocrine differentiation of canine anal sac glandular tumors. J Comp Path. 2013;149(2-3):199.

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