JPC SYSTEMIC PATHOLOGY
Signalment (JPC 2031602): A dog
HISTORY: This large mass was located lateral to the anus.
HISTOPATHOLOGIC DESCRIPTION: Anal sac: Effacing subepithelial connective tissue, partially surrounding the anal sac, replacing normal anal sac apocrine glands, infiltrating and compressing adjacent skeletal muscle, and compressing adjacent moderately ectatic anal sac apocrine glands is an unencapsulated, multilobulated, infiltrative, densely cellular neoplasm composed of polygonal cells arranged in multiple patterns including formation of variably sized islands and tubuloacini (tubular type), solidly cellular areas, and multifocal rosette and pseudorosette formation, on a coarse fibrovascular stroma. Neoplastic cells are cuboidal to columnar with variably distinct borders and moderate amounts of eosinophilic cytoplasm with rare apical blebbing. Nuclei are round to oval, located basally within tubuloacinar arrangements, and have finely stippled chromatin with 1-2 nucleoli. There is mild anisocytosis and anisokaryosis and the mitotic rate averages 2-3 per 40x high power field. Multifocally glandular lumina contain eosinophilic amorphous secretory product occasionally mixed with sloughed neoplastic cells and necrotic cellular debris. There is multifocal scattered single cell necrosis and hemosiderin-laden macrophages. Neoplastic cells are present within dilated lymphatic vessels. Neoplastic cells focally form a large single duct lined by multiple layers of columnar neoplastic cells that contains low numbers of erythrocytes, sloughed neoplastic cells, hemosiderin-laden macrophages, and fibrous connective tissue with necrotic cellular debris. Multifocally the periglandular and subepithelial connective tissue surrounding the neoplasm is infiltrated by 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 (also see D-N06)
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)
- Most common malignant perianal tumor in dogs; no sex predilection
- Highly malignant; highly invasive; have often metastasized to regional lymph nodes (sublumbar and sacral) +/- lung, spleen, liver, and bone at time of clinical presentation
- Commonly causes humoral hypercalcemia of malignancy (HHM) via ectopic hormone production of markedly elevated levels of parathyroid hormone-related protein (PTHrP)
- Paraneoplastic hypercalcemia is associated with shorter survival
- This is the second most common tumor in dogs associated with PTHrP-associated hypercalcemia (lymphoma is the most common cause of HHM)
- HHM: mediated by humoral factors (e.g. PTH, PTHrP, cytokines, steroids, prostaglandins) released by either tumor cells or normal host cells; these factors act systemically and distant to the tumor
- Humoral factors induce hypercalcemia by increasing osteoclastic bone resorption, increasing calcium reabsorption from the kidney, and/or increasing calcium absorption from the intestine
- Increased osteoclastic bone resorption distant to the site of the neoplasm is the most consistent feature of HHM
- Anal sac gland carcinoma tumor cells secrete markedly elevated levels of PTHrP
- PTHrP is normally produced in the body and acts as a paracrine regulator
- PTHrP binds PTH1 receptors in bone and kidney with similar affinity of PTH
- Humoral factors (IL-1, tumor necrosis factors, and transforming growth factor alpha) are additive or synergistic with PTHrP
- Increased PTHrP à binding to and activating PTH1 receptors in bone and kidney à hypercalcemia and hypophosphatemia via:
- 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
TYPICAL CLINICAL FINDINGS:
- Tenesmus, constipation, perineal pruritus
- Clinical signs of hypercalcemia - polyuria/polydipsia, muscle weakness, cardiac arrhythmia, anorexia, vomiting, renal failure
- Clinical pathology: Persistent hypercalcemia, hypophosphatemia, hypercalciuria, hyperphosphaturia
- Increased osteoclastic bone resorption distant from site of neoplasm
- Hypercalcemia and hypophosphatemia normalize following complete surgical excision
- Cytology: Aspirates are often highly cellular and contain many free, intact, nuclei (naked nuclei), and scattered loose clusters of cells with indistinct cell borders that occasionally form acinar like structures. Anisokaryosis is often mild despite aggressive nature.
TYPICAL GROSS FINDINGS:
- Perineal mass ventrolateral to the anus; unilateral or bilateral; poorly demarcated; overlying epidermis is usually not attached to mass; rarely invades the rectum or anus; expansile mass that arises from the anal sac wall and compresses/projects into the lumen
- May be incidental finding on physical exam (only 50% of cases have a grossly visible perianal mass)
- Cut surface is tan, lobulated, with multiple cysts
- Due to HHM:
- 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: (most are bimorphic with solid and glandular areas)
- Solid type: Sheets and packets of monomorphic polygonal cells with scant eosinophilic cytoplasm and round/oval hyperchromatic nuclei separated by thin fibrovascular stroma
- Rosette type: Basally located nuclei and eosinophilic cytoplasm; radially arranged around a small central focus of eosinophilic secretion (rosette-like)
- Tubular type: Glandular acini with projections of apical cytoplasm into the lumen; larger cuboidal cells with abundant eosinophilic cytoplasm and hyperchromatic nuclei; form large tubular lumens filled with eosinophilic secretion
- Prominent desmoplastic response if locally invasive
- Tumor cell emboli in lymphatics and veins
- Kidney – renal mineralization in approximately 90% of HHM
ADDITIONAL DIAGNOSTIC TESTS:
- IHC: CK7+/CK14- (Pieper, J Vet Diag Inv 2015); weakly positive for PTHrP and variably positive for chromogranin A (suggests neuroendocrine differentiation)
- Cytology: Typically highly cellular, composed of loosely cohesive clusters of cells often with free, intact nuclei forming occasional acinar-like structures
- Criteria for the diagnosis of hypercalcemia of malignancy include:
- Persistent hypercalcemia and hypophosphatemia
- Absence of radiographic/pathologic evidence of tumor metastasis in bone
- Atrophy of the parathyroid glands and diffuse nodular hyperplasia of thyroid C cells
- Remission of hypercalcemia when the tumor is destroyed or excised
Microscopically – Perianal neoplasia:
- Anal sac gland adenoma: Low mitotic activity; well demarcated; 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+ (Pieper, J Vet Diag Inv 2015)
- Perianal gland (hepatoid) epithelioma: Mostly basaloid cells with mitotic activity, but little atypia
- Perianal gland (hepatoid) carcinoma: Pleomorphic, disorganized basaloid and hepatoid cells with mitotic activity and invasive growth
- Cutaneous sebaceous and apocrine tumors
- Squamous cell carcinoma of the anal sac
- Neuroendocrine carcinoma of the apocrine glands of the anal sac (immunoreactive for chromagranin and synaptophysin)
- Canine clitoral carcinoma has very similar histologic appearance (Ranieri, Vet Path 2018)
Clinically – Hypercalcemia: HARDIONS-T
- Primary Hyperparathyroidism (low/normal serum P) or Hyperproteinemia
- HypoAdrenocorticism (Addisons) or Acidosis
- Renal disease (renal failure in horses; lhasa apsos familial renal disease)
- Hypervitaminosis D: Will have hyperphosphatemia (ingestion of calciferol-containing rodenticides, ingestion of plants containing vitamin D glycosides: Solanum malacoxylon (AKA Solanum glaucophyllum), Cestrum diurnum, Trisetum flavescens)
- Immobilization or Idiopathic
- Osteolytic lesions (osteomyelitis; metastatic neoplasia)
- Neoplasia: Lymphoma (most common cause of tumor-associated hypercalcemia), Multiple myeloma, carcinomas (ex. gastric SCC in horses), anal sac gland carcinoma
- Spurious: Granulomatous diseases: macrophage secretion of vitamin D analogs; Blastomycosis, Johne’s disease
- Thiazide diuretics
- Cats: Apocrine gland carcinomas of the anal sac occur infrequently in cats and HHM does not occur in association
- 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
- Capen CC. Endocrine glands. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 3. 6th ed. Philadelphia, PA:Elsevier; 2016:307-308.
- 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.
- 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.
- 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.
- Mauldin EA, Peters-Kennedy J. Integumentary system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. 5th ed. Philadelphia, Pennsylvania: Elsevier; 2015:720.
- 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.
- Ranieri V, Cian F, Stewart J, et al. Canine clitoral carcinoma: A clinical, cytologic, histopathologic, immunohistochemical, and ultrastructural study. Vet Path. 2018: 55(4): 501-509.