JPC SYSTEMIC PATHOLOGY
ENDOCRINE SYSTEM
January 2022
R-N12

Signalment:   A 10-month-old Fischer 344 rat

 

HISTORY:  Incidental finding in an aging rat study.

 

HISTOPATHOLOGIC DESCRIPTION:  Uterus:  Originating from and markedly expanding the endometrial stroma up to 2.5mm, compressing the uterine lumen, and compressing the uterine wall, is a circumferential, densely cellular proliferation of cells with several different morphologies arranged in variably well demarcated zones. Peripherally and most prominently at the antimesometrial aspect of the uterus, extending a third of the way around the uterus, is the basal zone that separates the myometrium from the proliferative decidual cells and is composed of remnants of the endometrial stroma and glands and few scattered lymphocytes. The inner aspect of the basal zone merges with a thin capsule that separates it from the proliferative decidual cells; this capsule is composed of an indistinct, thin band of spindle cells. The antimesometrial region of proliferative decidual cells is composed of densely packed, polygonal cells separated into packets by small capillaries; these cells have abundant eosinophilic, microvacuolated cytoplasm, large, round, vesiculate nuclei with prominent nucleoli, and are often binucleate. Mitotic figures in this region average 1 per individual HPF (0.237 sq mm). The mesometrial region of proliferative dedicual cells is composed of two cell populations: loosely packed spindle to stellate cells with prominent cytoplasmic processes ("spiny cells"), and scattered round cells with prominent eosinophilic granules (granulated metrial gland cells) separated by clear space. Mitoses and binucleate cells are frequent in both cell populations. The glycogenic area lies between the antimesometrial and mesometrial regions and encircles the uterine lumen. Though not prominent in this section, it is composed of plump polygonal cells separated by prominent vascular sinuses and separated by clear space toward the periphery. Nuclei are vesiculate and often binucleate, with prominent nucleoli and a mitotic average of 1 per individual HPF (0.237 sq mm). 

Urinary bladder; kidney; ovary; oviduct; urethra; and vagina: No significant lesions.

MORPHOLOGIC DIAGNOSIS:  Uterus: Decidual reaction, Fischer 344 rat, rodent.

SYNONYM:  Deciduoma (obsolete term)

GENERAL DISCUSSION:

• Non-neoplastic proliferation of decidual tissue that resembles pregnancy implantation; usually in young pseudopregnant rats; occurs in response to nonspecific stimuli; mimics normal decidual implantation sites; has a high degree of structural organization
  • The National Toxicology Program recommends that the term “deciduoma” be discontinued and the lesion renamed “decidual reaction”
• Decidual cells are endometrial stromal fibroblasts that re-differentiate during pregnancy to allow for trophoblasts to survive and grow, forming deciduate placentas
• Composed of six distinct regions (not all may be discernible due to the cut or stage of development): Basal zone, capsule, antimesometrial region, mesometrial region, glycogenic region, and metrial gland area (see light microscopic findings)

PATHOGENESIS:

• The cause is unknown but it is believed to be associated with pseudopregnancy and nonspecific stimuli
• Sensitization to decidualizing stimuli occurs at day 3-4 of pseudopregnancy- there must be at least 48 hours of exposure to progesterone, followed by small amounts of estrogen; the luminal epithelium has the ability to proliferate when stimulated and induces stromal differentiation and decidual reaction
• Nonspecific stimuli includes mechanical and electrical stimuli; endometrial trauma; intrauterine injections of various substances including balanced salt solutions, oily fluids, and air; vitamin E deficient diets
• This proliferative reaction has a defined, limited course; it ends in degeneration of decidual cells and spontaneous regression in about 12 days; the normal life span of rat decidual reaction is from day 4 until day 12-16 of pseudopregnancy
• Antimesometrial region develops first, followed by mesometrial region, and then metrial gland; decidual reaction regression occurs in the same order
• Low incidence of spontaneous decidual reactions

TYPICAL CLINICAL FINDINGS:  None

TYPICAL GROSS FINDINGS:

• Unilateral or bilateral, single or multiple nodules within the uterine horn that measure up to 4 mm in diameter; occasional diffuse uterine horn enlargement
• Endometrial ulceration
• Hyperemic mesometrial vessels within the broad ligament

TYPICAL LIGHT MICROSCOPIC FINDINGS:

High level of structural organization; composed of six layers:

• Basal zone
  • Outermost layer; separates decidual reaction from myometrium
  • Most prominent on the antimesometrial side (side of uterine horn opposite reflection of mesometrium); may extend 3/4 way around the endometrium
  • Composed of remnants of endometrial stroma and glands, which proliferate and reform the endometrium following regression of the decidual reaction
  • Few lymphocytes, macrophages, and eosinophils
• Capsule
  • Between basal zone and antimesometrial area; band of flattened cells that blend gradually with the endometrial cells on the antimesometrial side
  • Source of appositional growth
  • During decidual reaction regression, capsular necrosis separates the decidual reaction from the uterine wall, while preserving the basal zone
• Antimesometrial region
  • Densely packed polygonal, eosinophilic antimesometrial cells separated by small, radially oriented and cross-linked capillaries
  • Cells are often binucleate and may exceed 30um in diameter
• Mesometrial region - two cell types
  • Spiny mesometrial cells: Cytoplasm has long processes and abundant glycogen; cells are usually binucleate
  • Granulated metrial gland (GMG) cells: Large round cells that are up to 40 um in diameter and frequently binucleated; numerous, up to 2um diameter, PAS-positive, diastase-resistant eosinophilic granules in the cytoplasm
• Glycogenic area
  • Transition between antimesometrial and mesometrial regions
  • Bilaterally symmetrical areas with prominent vascular sinusoids
  • Glycogen is present, but not in large amounts
  • Stromal cells resemble loosely arranged spiny mesometrial cells
• Metrial gland - two cell types
  • Located within the mesometrial triangle (bordered by longitudinal muscle on two sides and circular muscle on the third side)
  • Granulated metrial gland (GMG) cells: Loosely arranged; whorl around vessels; natural killer (NK) cell lineage
  • Fibroblastic stromal cells: Adjacent to or surround the GMG cells

DIFFERENTIAL DIAGNOSIS:

Nodular lesions in the uterus of a rat:

• Decidual alteration: Occurs in aged rats secondary to endometrial irritation (i.e. endometrial or myometrial tumors); lacks well-defined structure
• Implantation site in pregnant uterus: Looks much like a decidual reaction but has a rapidly expanding implantation cavity
• Granular cell tumor: Polygonal cells with cytoplasmic granules; PAS +, diastase resistant
• Endometrial adenoma / adenocarcinoma: Polygonal cells arranged in acini and tubules, scirrhous response
• Endometrial stromal polyp: Polypoid mass protruding into the uterine lumen; edematous and collagenous stroma covered by endometrial epithelium; highly vascular; +/- cystic endometrial glands
• Leiomyoma / leiomyosarcoma: Spindle cells; cigar-shaped nuclei; positive for smooth muscle immunohistochemical markers

COMPARATIVE PATHOLOGY:

Decidual reaction:  Reported in the mouse, hamster, rabbit, dog, guinea pig and monkey

• Mouse: Similar pathology and histology as rats; induced on day 3-5 of pseudopregnancy; lasts 4 days; mouse GMG cells are twice as large as rat GMG cells, with larger granules
• Hamster: Decidual reaction does not produce a metrial gland, but a "vascular knot" within the mesometrial triangle develops instead
• Rabbit: Decidual reaction life span of 26 days (longer than in other species)
• Dog: Spontaneous pseudo-placentational endometrial hyperplasia (PEH; R-M08) which occurs in the luteal phase may be induced by bacteria from the vagina that stimulate the endometrium like a fertile ovum
  • Other sterile material within the lumen of the uterus during the luteal phase of a bitch can induce decidual reactions

Deciduosarcoma:

• Rare neoplasms unique to rabbits; composed of anaplastic decidualized endometrial stromal cells with invasive growth and neoplastic emboli

REFERENCES:

1. Cooper TK, Adelsohn D, Gilbertson SR. Spontaneous deciduosarcoma in a domestic rabbit (Oryctolagus cuniculus). Vet Pathol. 2006:43(3)377-380.
2. Katsuhhiko Y, Emoto Y, Kinoshita Y, et al. Histopathological and immunohistochemical characterization of spontaneously occurring uterine deciduomas in young adult rats. J Toxicol Pathol. 2013;26:61-66.
3. Laik-Schandelmaier C, Klopfleisch R, Schoniger S, et al. Spontaneously arising tumours and tumour-like lesions of the cervix and uterus in 83 pet guinea pigs (Cavia porcellus). J Comp Pathol. 2017;156:339-351.
4. National Toxicology Program Nonneoplastic Lesion Atlas. https://ntp.niehs.nih.gov/nnl/female_reproductive/uterus/decreac/index.htm. Accessed 20 January 2020.
5. Robles TG, et al. Hoxa-10 and cyclin D3 overexpression in the decidual reaction in a superovulation protocol in young adult C57BL/6J mice. Vet Pathol. 2017;54(2):328-335.
6. Schlafer DH, Foster RA. Female genital system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 3. 6th ed. St. Louis, MO: Elsevier Saunders; 2016:383.

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