JPC SYSTEMIC PATHOLOGY
ENDOCRINE SYSTEM
January 2022
R-N09

SIGNALMENT (JPC #2843592):  Female rat

HISTORY:  None

HISTOPATHOLOGIC DESCRIPTION:  Haired skin with clitoral gland:  Markedly expanding the clitoral gland and centered on the markedly ectatic, keratin-filled main clitoral gland excretory duct is a 1.5 cm, encapsulated, well circumscribed, moderately cellular neoplasm composed of epithelial cells forming a peripheral basaloid reserve layer that progresses into either secretory glandular epithelial cells or squamous (ductal) epithelial cells. Neoplastic cells are arranged in broad cords, variably sized acini and cysts, islands, and trabeculae on a fine but markedly edematous fibrovascular stroma.  Neoplastic cells have indistinct borders and a moderate amount of eosinophilic, fibrillar to microvacuolated cytoplasm that in secretory glandular cells is often obscured by numerous brightly eosinophilic, intracytoplasmic globules (secretory product) and in squamous epithelial (ductular) cells often contains basophilic keratohyaline granules (gradual keratinization).  Nuclei are oval with finely stippled chromatin and a single distinct magenta nucleolus.  Anisocytosis and anisokaryosis are mild.  Mitoses average 5 per 0.237mm² (1 HPF).  The neoplastic cyst and acinar lumina contain degenerating cells and eosinophilic, flocculent secretory product admixed with neutrophils, macrophages, and hemorrhage, fibrin, and edema.  Neoplastic cells undergoing ductal (squamous) differentiation surround a central duct containing the previously described secretory product and degenerating cells as well as lamellated keratin, low numbers of neutrophils, scant hemorrhage, fibrin, and edema, and small colonies of cocci. The main clitoral gland excretory duct is markedly ectatic, hyperkeratotic, and confluent with the neoplasm and contains similar debris, lamellated keratin, and secretory product.  Within the overlying subcutis and dermis, there are multifocal infiltrates of few scattered Iymphocytes and plasma cells. 

MORPHOLOGIC DIAGNOSIS:  Clitoral gland:  Adenoma, strain not specified rat, rodent.

SYNONYM(S): Preputial gland adenoma

GENERAL DISCUSSION:

• Clitoral, preputial, circumanal, and Zymbal’s glands are specialized sebaceous glands; they are compound, holocrine, branched, and tubuloalveolar
• Female clitoral glands are located lateral to the vaginal opening; male preputial glands are craniolateral to the penis and often appear more cystic than female clitoral glands
• Acini open into numerous lateral ducts that fuse into a wide central duct, which becomes the excretory duct
• Ducts are lined by keratinizing stratified squamous epithelium
• In rats, cells have large intracytoplasmic eosinophilic granules that contain pheromones and beta-glucuronidase; these are not present in mice; however, the cytoplasm appears brightly eosinophilic
• Neoplasms can develop from the acinar cells, basal cells, or the squamous epithelium
  • Adenoma and adenocarcinoma from acinar cells
  • Squamous cell papillomas from ductal cells
  • Basal cell carcinoma from basal cells
• Aged rats (15 to 30 months) of various strains are affected
• Spontaneous clitoral gland neoplasms: 15% in F344 rats; 21% in Wistar rats; <1% in Harlan Sprague-Dawley rats

TYPICAL GROSS FINDINGS: 

• Firm subcutaneous masses in the perineum lateral to the penis or ventral to the vaginal orifice; sometimes ulcerated

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Adenomas and carcinomas may be subdivided by pattern (solid, cystic, and papillary) and cellular differentiation (glandular, basal, squamous, and mixed), but subtyping is not recommended in regulatory toxicity studies
• No differences in biologic behavior between the patterns
• Neoplasms with more than one pattern are classified by the predominant cell type
• Adenomas are well circumscribed
• Carcinomas are locally invasive; metastases to regional lymph nodes and lungs occur rarely
• Acinar cell neoplasms have cells with brightly eosinophilic cytoplasmic granules

DIFFERENTIAL DIAGNOSIS:

• Hyperplasia: cells more uniform, no capsule
• Carcinoma, mixed cell subtype: mixture of squamous and sebaceous cells, invasion of surrounding tissue, cellular atypia, frequent mitoses
• Carcinoma, squamous cell: Derived from ductal cells, no acinar involvement, rare
• Preputial gland abscess

COMPARATIVE PATHOLOGY:

• Dog: clitoral carcinomas are rare; however, overlapping features with apocrine gland anal sac adenocarcinoma make diagnosis challenging; may have neuroendocrine differentiation
  • Histologic features consistent with malignant cells of apocrine gland origin
  • Subtypes: tubular, solid, rosette type
  • Immunohistochemistry: Neuron specific enolase was recently positive in 6 out of 6 cases (Verin, Vet Pathol. 2018)
  • One case study where a dog developed a secondary hypercalcemia of malignancy (Neihaus, J Am Animal Hosp Assoc. 2010)
• Mice: Rare reports of spontaneous adenocarcinoma of the clitoral and preputial glands

REFERENCES:

1. Barthold SW, Griffey SM, Percy DH. Pathology of Laboratory Rodents and Rabbits. 4^th Ames, IA: John Wiley and Sons, Inc. 2016:164.
2. Brix AE, Nyska A, Haseman JK, Sells DM, Jokinen MP, Walker NJ. Incidences of selected lesions in control female Harlan Sprague-Dawley rats from two-year studies performed by the National Toxicology Program. Toxicol Pathol; 2005(33):477-83.
3. Neihaus, SA, Winter JE, Goring RL, Kennedy FA, Kuipel, M. Primary Clitoral Adenocarcinoma with Secondary Hypercalcemia of Malignancy in a Dog. J Am Animal Hosp Assoc; 2010(46):193-196.
4. Rudmann D, Cardiff R, Chouinard L, Goodman D, Küttler K, Marxfeld H, Molinolo A, Treumann S, Yoshizawa K; INHAND Mammary, Zymbal's, Preputial, and Clitoral Gland Organ Working Group. Proliferative and nonproliferative lesions of the rat and mouse mammary, Zymbal's, preputial, and clitoral glands. Toxicol Pathol. 2012;40(6 Suppl):7S-39S.
5. Seely JC, Boorman GA. Mammary gland and specialized sebaceous glands. In: Maronpot RR, Boorman GA, Gaul BW, eds. Pathology of the Mouse. Vienna, IL: Cache River Press; 1999:624-633.
6. Verin R, Cian F, Stewart J, Binanti D, MacNeill AL, Piviani M, Monti P, Baroni G, Le Calvez S, Scase TJ, Finotello R. Canine clitoral carcinoma: a clinical, cytologic, histopathologic, immunohistochemical, and ultrastructural study. Vet Pathol. 2018;55(4):501-509.

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