JPC SYSTEMIC PATHOLOGY

INTEGUMENTARY SYSTEM

September 2016

I-N08

 

Signalment (JPC 2031602):  A dog

HISTORY:  This large mass was located lateral to the anus.

HISTOPATHOLOGIC DESCRIPTION:  Anal sac:  Effacing subepithelial connective tissue, replacing normal apocrine glands, infiltrating and compressing surrounding muscle bundles, and compressing adjacent moderately ectatic apocrine glands is an unencapsulated, multilobulated, densely cellular neoplasm partially surrounding the anal sac and composed of bimorphic polygonal cells with glandular portions arranged in variably sized islands and tubuloacini, and more solidly cellular areas with multifocal rosette and pseudorosette formation. Neoplastic cells are cuboidal to columnar with variably distinct borders, moderate amounts of eosinophilic cytoplasm, and multifocal apical blebbing and are supported by a coarse fibrovascular stroma. Nuclei are round to oval, located basally within tubuloacinar arrangements, and have finely stippled chromatin with 1-2 nucleoli. There is mild anisokaryosis and the mitotic rate averages 2-3 per high power field. Multifocally glandular lumina contain eosinophilic amorphous secretory product occasionally mixed with sloughed neoplastic cells and necrotic cellular debris. Neoplastic cells form a large single duct lined by multiple layers of columnar neoplastic cells and is filled with low numbers of erythrocytes, sloughed neoplastic cells, hemosiderin-laden macrophages, and fibrous connective tissue with necrotic cellular debris. Neoplastic cells are found within dilated lymphatics. There is multifocal scattered single cell necrosis and hemosiderin-laden macrophages. Multifocally in the periglandular and subepithelial connective tissue surrounding the neoplasm, there are moderate numbers of lymphocytes, plasma cells, and fewer eosinophils. Subjacent to the hyperpigmented and mildly hyperplastic anal sac epithelium are multifocal melanin-laden macrophages (pigmentary incontinence).

MORPHOLOGIC DIAGNOSIS:  Anal sac:  Adenocarcinoma of the apocrine glands of the anal sac, breed not specified, canine.

CONDITION:  Adenocarcinoma of the apocrine glands of the anal sac

SYNONYMS:  Adenocarcinoma of the apocrine glands of the anal sac (AAGAS)

                          Anal sac gland carcinoma (ASGC)

                          Carcinomas of the apocrine glands of the anal sac (CAGAS)

                          Anal sac apocrine gland adenocarcinoma (ASAGAC)

 GENERAL DISCUSSION:

• The most common malignant tumor in the perineum of dogs; historically thought to affect primarily older female dogs (median age 10 years old)(1981); however, recent studies (2003) show no sex predilection
• Highly malignant; highly invasive; have often metastasized to regional lymph nodes (sublumbar and sacral) and/or abdominal and thoracic viscera at time of clinical presentation
• Produces greatly elevated levels of parathyroid hormone-related protein (PTHrP) which results in hypercalcemia and hypophosphatemia: Humoral hypercalcemia of malignancy (HHM)
• Second most common cause of tumor-associated hypercalcemia (lymphoma is the number one cause both tumor and non-tumor) (second most common non-tumor is renal failure/secondary hyperparathyroidism)
• Highest Ca²⁺ concentrations due to lymphoma and anal sac adenocarcinoma

PATHOGENESIS: 

• HHM is mediated by humoral factors released by either tumor cells or normal host cells that act systemically and distant to the tumor
• Humoral factors associated with HHM (PTH, PTHrP, cytokines, steroids, prostaglandins) may increase osteoclastic bone resorption, calcium reabsorption from the kidney (decreased fractional Ca⁺⁺ excretion) or calcium absorption from the intestine
• PTHrP is nearly identical in biological activity to parathyroid hormone (PTH) and is widely produced in the body by adult tissues in small amounts – normally acts as paracrine factor
  • Stimulate adenylate cyclase, phospholipase C
• Increased PTHrP results in hypercalcemia and hypophosphatemia by binding to and activating PTHrP/PTH receptors in bone and kidney:
  • Stimulates osteoclastic bone resorption
  • Increases calcium reabsorption in the renal tubules
  • Decreases phosphorous reabsorption in the renal tubules
  • Activates vitamin D precursors, increasing intestinal absorption of calcium
• Humoral factors (IL-1, tumor necrosis factors, and transforming growth factor alpha) are additive or synergistic with PTHrP

TYPICAL CLINICAL FINDINGS: 

• Tenesmus, constipation, perineal pruritus
• Polyuria/polydipsia (inhibition of ADH-dependent resorption of NaCl by hypercalcemia), bradycardia, muscle weakness, anorexia, vomiting
• Clinical pathology: Persistent hypercalcemia, hypophosphatemia, hypercalciuria, hyperphosphaturia
• Increased osteoclastic bone resorption distant from site of neoplasm
• Hypercalcemia and hypophosphatemia normalize following complete surgical excision

TYPICAL GROSS FINDINGS: 

• Perineal mass, ventrolateral to the anus; usually unilateral; overlying epidermis is usually mobile and rarely ulcerated
• Can be occult, growing cranially within the pelvic canal; may be incidental finding on physical exam
• Rarely invades the rectum or anus; expansile mass that compresses the lumen
• Epidermis of the anal sac is often hyperpigmented and the mass is white to tan
• Cut surface is tan, lobulated; multiple cysts
• Atrophy of parathyroid glands and nodular hyperplasia of thyroid C-cells
• Metastatic renal calcification, especially at the corticomedullary junction and renal tubular (collecting system most affected) degeneration (direct hypercalcemic toxicity or ischemia from vasoconstriction); +/- mineralization of fundic gastric mucosa and endocardium (due to mass law Ca x Phos > 70)

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Three patterns:
  • Solid type: Tumor cells with scant cytoplasm separated by thin bands of fibrous connective tissue
  • Rosette type: Basally located nuclei and eosinophilic cytoplasm; radially arranged around a small central focus of eosinophilic secretion (rosette-like)
  • Tubular type: Cuboidal cells with abundant eosinophilic cytoplasm forminglarge tubular lumens containing eosinophilic secretion
• Prominent desmoplastic response if locally invasive

ADDITIONAL DIAGNOSTIC TESTS: 

• Criteria for the diagnosis of hypercalcemia of malignancy include:
  • Persistent hypercalcemia and hypophosphatemia
  • Absence of radiographic/pathologic evidence of tumor metastases in bone
  • Atrophy of the parathyroid glands and diffuse nodular hyperplasia of thyroid C cells
  • Remission of hypercalcemia when the tumor is destroyed or excise
• IHC: CK7+/CK14- according to 2015 JVDI article

DIFFERENTIAL DIAGNOSIS:

• Microscopically – Perianal neoplasia:
  • Anal sac gland adenoma: Low mitotic activity; well encapsulated; rare
  • Perianal gland (hepatoid) adenoma (80%):  Common in old, intact male dogs; well organized trabeculae of polygonal cells with abundant granular cytoplasm and peripheral reserve cells; little atypia; CK7-/CK14+ according to 2015 JVDI article
  • Perianal gland (hepatoid) epithelioma:  Mostly basaloid cells with mitotic activity, but little atypia
  • Perianal gland (hepatoid) carcinoma:  Pleomorphic basaloid and hepatoid cells with mitotic activity and invasive growth
  • Sebaceous and apocrine tumors
  • Squamous cell carcinoma of the anal sac
  • Neuroendocrine carcinoma of the apocrine glands of the anal sac (pos for chromagranin and synaptophysin)

• Clinically – Hypercalcemia: HARDIONS-T
  • Primary Hyperparathyroidism: Will have low to normal serum P
  • HypoAdrenocorticism (Addisons) or Acidosis
  • Renal disease (renal failure in horses, rare in dogs)
  • Hypervitaminosis D: Will have hyperphosphatemia (Ingestion of calciferol-containing rodenticides, Ingestion of plants containing vitamin D glycosides: Solanum malacoxylon, Cestrum diurnum, Trisetum flavescens)
  • Immobilization
  • Osteolytic lesion
  • Neoplasia: Lymphoma: Most common cause of tumor-associated hypercalcemia (due to osteoclast-activating factors), Multiple myeloma; carcinomas (ex. gastric SCC in horses), anal sac carcinoma, benign renal angiomyxoma
  • Spurious: Granulomatous diseases: macrophage secretion of vitamin D analogs; Blastomycosis, Johne’s disease
  • Thiazide diuretics

And

• Familial renal disease in dogs: Young lhasa apsos
• Bone disease with osteolysis: Septic osteomyelitis; metastatic neoplasia
• Hyperproteinemia

COMPARATIVE PATHOLOGY:

• HHM has also been reported in cats, horses, mink; in VX₂ carcinoma of rabbits; fibrosarcoma of mice (both produce PGE₂); Leydig cell tumor in rats; and gastric carcinoma in a horse
• Anal sac gland carcinoma (xenograft) from dogs is used in nude mice (CAC-8) models for the study of human HHM

REFERENCES:

1. Capen CC. Endocrine glands. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 3. 6th ed. Philadelphia, PA:Elsevier; 2016:308.
2. Capen CC. Tumors of the endocrine glands. In: Meuten DJ, ed. Tumors in Domestic Animals. 4th ed. Ames, IA: Iowa State University Press; 2002:672-679.
3. Capen CC, La Perle KM. Endocrine system. In: McGavin MD, Zachary JF, eds. Pathologic Basis Veterinary Disease.  6th ed. St. Louis, MO: Mosby; 2017:719.
4. Cockerell GL, Cooper BJ. Disorders of cell growth and cancer biology. In: Slauson DO, Cooper BJ, eds. Mechanisms of Disease a Textbook of Comparative General Pathology.3rd ed. St. Louis, MO: Mosby; 2002:356-357.
5. Ferguson DC, Hoenig M: Endocrine system. In: Latimer KS, Mahaffey EA, Prasse KW , eds. Duncan and Prasse’s Veterinary Laboratory Medicine: Clinical Pathology. 5th ed. Ames, IA: Iowa State University Press; 2011:300-301.
6. Goldschmidt MH, Dunstan RW, Stannard AA, von Tscharner C, Walder EJ, Yager JA. Schulman FY, ed. Histological Classification of Epithelial and Melanocytic Tumors of the Skin of Domestic Animals. 2nd series, Vol. 3. Washington, DC: Armed Forces Institute of Pathology; 1998:31.
7. Goldschmidt MH, Hendrick MJ. Tumors of the skin and soft tissues. In: Meuten DJ ed. Tumors in Domestic Animals. 4th ed. Ames, IA: Iowa State Press; 2002:74-76, 674-679.
8. Parry NM. Anal sac gland carcinoma in a cat. Vet Pathol. 2006;43:1008-1010.
9. 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 Diag Inv. 2015: 27(4): 497-503.
10. Polton GA, Brearley MJ. Clinical stage, therapy, and prognosis in canine anal sac gland carcinoma. J Vet Intern Med. 2007;21(2):274-280.
11. Suzuki K, Morita R, Nomura K, Shibutani M, Mitsumori K. Immunohisochemical characterization of neuroendocrine differentiation of canine anal sac glandular tumors. J Comp Pathol. 2013;149(2-3):199-207.

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