Equine Ovarian Abnormalities: Granulosa-Theca Cell Tumor – NAVLE Study Guide

Overview and Clinical Importance

Granulosa-theca cell tumors (GCTs) are the most common ovarian neoplasms in mares, representing approximately 2.5 to 5 percent of all equine tumors and more than 85 percent of ovarian tumors in horses. These

sex cord-stromal tumors arise from granulosa cells alone or in combination with theca cells. While nearly always benign and unilateral, GCTs significantly impact mare behavior, reproductive performance, and athletic ability through abnormal hormone production. Understanding the pathophysiology, clinical presentation, diagnostic approach, and surgical management of GCTs is essential for NAVLE candidates, as these tumors present with highly testable clinical scenarios involving hormonal disturbances and behavioral changes.

Etiology and Pathophysiology

Tumor Origin and Classification

Sex cord-stromal tumors of the ovary develop from granulosa cells, which are normally responsible for supporting oocyte development and producing estrogen. When theca cells are also present, the tumor is specifically termed a

granulosa-theca cell tumor (GTCT). These neoplastic cells retain their hormone-producing capabilities but lose normal feedback regulation, leading to excessive and inappropriate hormone secretion.

Hormonal Dysfunction

GCTs produce variable combinations of reproductive hormones, creating diverse clinical presentations. The primary hormonal abnormalities include:

Inhibin: Markedly elevated in approximately 80 to 90 percent of cases. Inhibin suppresses pituitary follicle-stimulating hormone (FSH) secretion through negative feedback, preventing follicular development in the contralateral ovary.

Anti-Müllerian Hormone (AMH): Produced by proliferating granulosa cells. AMH is the most sensitive biomarker for GCT diagnosis, with 98 percent sensitivity. Normal mares have AMH concentrations less than 1 ng per mL, while GCT-affected mares typically have levels greater than 10 ng per mL and often greater than 60 ng per mL.

Testosterone: Elevated in approximately 50 percent of cases, with levels greater than 100 pg per mL considered diagnostic. Testosterone elevation causes masculinization and stallion-like behavior.

Estrogen and Progesterone: Variably elevated or normal. Some tumors produce predominantly estrogen, causing persistent estrus, while others produce minimal hormones.

Epidemiology

Age and Breed Distribution

GCTs affect mares of all ages and breeds, but certain patterns exist. The mean age at diagnosis is approximately 9 to 11 years, with a reported range from 2 to 20 years. Juvenile cases have been documented in mares as young as 2 years old. Unlike many

neoplasms that predominantly affect aged animals, GCTs commonly occur in middle-aged, reproductively active mares aged 5 to 9 years. There is no apparent breed predilection, and tumors have been reported in pregnant mares, though this is rare.

Laterality and Bilaterality

Approximately 95 percent of GCTs are unilateral, with equal distribution between left and right ovaries. Bilateral GCTs occur in less than 5 percent of cases and may be concurrent or develop years apart on opposite ovaries. When bilateral, both ovaries are typically enlarged, though asymmetry may still be present.

Clinical Signs and Presentations

The clinical manifestations of GCTs are highly variable and depend on the hormonal profile of the individual tumor. Mares may present with behavioral abnormalities, reproductive dysfunction, performance issues, or no clinical signs at all.

Behavioral Changes

Stallion-like Behavior (Masculinization): Associated with elevated testosterone. Affected mares display mounting behavior toward other mares, herding and driving behavior, increased aggression, squealing, striking, stallion-like vocalizations, and development of a cresty neck with increased muscle mass in chronic cases.

Increased Aggression: Mares may become aggressive toward herd-mates they previously tolerated, exhibit biting or kicking behavior, show threatening behavior toward handlers, and demonstrate general irritability or crankiness.

Behavioral Inconsistency: Some mares show no behavioral changes despite having a confirmed GCT, particularly when the tumor is nonfunctional or produces hormones that do not cause overt behavioral effects.

Reproductive Abnormalities

Anestrus: The mare fails to show cyclical behavior or estrus signs. This is the most common reproductive presentation, occurring when inhibin suppresses FSH and prevents follicular development on the contralateral ovary.

Persistent or Prolonged Estrus: Continuous estrous behavior or extended cycles with short periods of diestrus, typically associated with estrogen-secreting tumors.

Irregular Estrous Cycles: Erratic patterns that do not follow normal 21-day cycles, with unpredictable transitions between estrus and diestrus.

Breeding Failure: Mares intended for breeding fail to conceive due to lack of ovulation from the inactive contralateral ovary.

Performance-Related Issues

Performance horses with GCTs may present for evaluation of vague lameness or discomfort rather than reproductive complaints. Important performance-related signs include:

Reluctance to move forward, particularly at speed or when jumping

Resistance to pressure in the flank region

Refusal of certain gaits or leads

Back soreness or suspected saddle fit problems

Kicking out when asked to perform specific movements

General irritability or poor attitude during work

These signs result from discomfort caused by the enlarged ovary placing tension on the ovarian ligaments (mesovarium and broad ligament), particularly during athletic activity. The tumor's weight creates a pulling sensation that worsens with movement.

Rare Complications

Hemoabdomen: Rarely, GCTs rupture and hemorrhage into the abdominal cavity, causing acute signs of blood loss including pale mucous membranes, tachycardia, lethargy or quiet demeanor, abdominal pain or colic signs, and potentially hypovolemic shock if hemorrhage is severe.

Diagnostic Approach

History and Physical Examination

A thorough history should document behavioral changes, reproductive performance, estrous cycle patterns, athletic performance issues, and duration of clinical signs. Physical examination findings may be unremarkable, but some mares exhibit muscle hypertrophy in the neck and shoulders if chronic testosterone elevation is present.

Rectal Palpation

Transrectal palpation is a critical diagnostic step and typically reveals characteristic findings:

Affected Ovary: The tumor-bearing ovary is enlarged, firm, and often nodular or lobulated. Size varies greatly, ranging from slightly larger than normal (5 to 8 cm) to massively enlarged (up to 40 cm or more in diameter). The

ovulation fossa is typically not palpable on the affected ovary. Tumor consistency may be firm or fluctuant depending on the degree of cystic change.

Contralateral Ovary: The unaffected ovary is almost always small (2 to 3 cm), firm, and inactive with no palpable follicular structures. This bilateral asymmetry with a small, inactive contralateral ovary is pathognomonic for GCT among ovarian abnormalities.

Transrectal Ultrasonography

Ultrasonographic examination provides detailed structural information about the ovaries. The classic appearance of a GCT is a

multicystic honeycomb pattern with multiple irregularly shaped anechoic (fluid-filled) areas separated by hyperechoic tissue, resembling a honeycomb structure. However, ultrasonographic appearance is highly variable:

Multicystic Honeycomb (Most Common): Multiple small to medium cysts creating characteristic honeycomb appearance with areas of solid tissue interspersed

Single Large Cyst: Solid ovarian mass with one dominant anechoic fluid-filled cyst

Dense Homogeneous: Uniformly echogenic solid mass with minimal cystic change

Hemorrhage or Necrosis: Areas of variable echogenicity representing hematoma or necrotic regions

Progressive Changes: Early GCTs may initially appear as a single enlarged follicle that later develops the classic honeycomb pattern as the tumor grows

The contralateral ovary appears small with no or minimal follicular activity.

Hormonal Assays

Serum hormone testing provides definitive diagnosis, particularly in cases where ultrasonographic findings are ambiguous or the tumor is in early stages. The following table summarizes diagnostic hormone levels:

Differential Diagnoses

Several conditions can mimic GCTs and must be differentiated:

Transitional Estrus: During spring and fall transitions, mares may develop large anovulatory follicles or multiple small follicles creating a honeycomb ultrasound appearance. These mares may show behavioral changes and hormonal fluctuations similar

to GCT. Distinguishing features include both ovaries showing some activity (not one enlarged and one inactive), normal or only mildly elevated hormone levels, and resolution over time as the mare enters or exits the breeding season.

Anovulatory Hemorrhagic Follicle: Can appear similar to GCT on ultrasound, particularly if the follicle contains blood and debris. However, the contralateral ovary remains active, and hormone levels are normal. Sequential ultrasound examinations show evolution or resolution.

Other Ovarian Tumors: Rare ovarian neoplasms including teratoma, dysgerminoma, cystadenoma, and lymphoma may cause unilateral ovarian enlargement. These tumors typically do not cause contralateral ovarian suppression and have normal hormone levels.

Ovarian Hematoma: May occur following trauma or spontaneous hemorrhage. The contralateral ovary remains functional, and there are no hormonal abnormalities.

Pathology and Histopathology

Gross Pathology

GCTs vary widely in size, from minimally enlarged ovaries to massive tumors weighing up to 17 kg (with rare reports of 59 kg). The

classic gross appearance when the tumor is sectioned reveals multiple cysts of varying sizes creating a honeycomb pattern, with areas of solid tan or yellow tissue representing granulosa and theca cell proliferation. Some tumors are predominantly solid with minimal cystic change, while others have one large dominant cyst.

The tumor surface may be smooth or lobulated. The ovulation fossa is typically obliterated. Areas of hemorrhage or necrosis may be present, particularly in large tumors. The tumor capsule is usually intact, though rare cases of rupture and hemoperitoneum occur.

Histopathology

Microscopic examination confirms the diagnosis. GCTs show variable structural patterns including:

Follicular Pattern: Structures resembling follicles with granulosa cells lining cystic spaces, mimicking normal follicles but without organization

Diffuse Pattern: Sheets of granulosa cells with no specific organization

Trabecular Pattern: Granulosa cells arranged in cords or trabeculae

Insular Pattern: Islands or nests of granulosa cells

Theca cells are present in varying numbers, with some tumors showing prominent theca cell proliferation. Sertoli-like cells and Leydig-like cells may be identified. The mitotic rate is typically low, consistent with benign behavior. Immunohistochemistry for AMH, inhibin, and calretinin can confirm the granulosa cell origin of the tumor.

Treatment

Surgical Management

Ovariectomy (surgical removal of the affected ovary) is the definitive treatment for GCTs. The choice of surgical approach depends on tumor size, surgeon expertise, and available facilities.

Surgical Considerations

Large tumors stretch the ovarian ligaments and vascular pedicle, making hemorrhage a significant concern during surgery. Careful ligation of the ovarian artery and vein is essential. The mesovarium (ovarian mesentery) must be thoroughly examined

to ensure complete hemostasis before closing. Rupture of the tumor during removal should be avoided to prevent seeding of tumor cells, though GCTs are benign and metastasis does not occur.

Postoperative Care

Typical postoperative management includes:

• Stall rest with hand walking for 10 to 14 days
• Gradual return to turnout and exercise over 2 to 4 weeks
• Antibiotics if indicated (typically 5 to 7 days)
• Non-steroidal anti-inflammatory drugs (NSAIDs) for pain management (3 to 7 days)
• Incision monitoring for swelling, discharge, or dehiscence

Prognosis and Return to Normal Function

Behavioral Recovery

Behavioral abnormalities typically resolve within weeks to months after tumor removal. Stallion-like behavior and aggression associated with testosterone-secreting tumors usually improve within 1 to 3 months as hormone levels normalize. Mares return to their previous temperament, though chronic muscle development (cresty neck) may persist.

Reproductive Recovery

The prognosis for return to fertility is excellent if one ovary was removed. The contralateral ovary, which was suppressed by inhibin from the tumor, typically resumes normal follicular activity and ovulation within

6 to 8 months after surgery. This delay occurs because the ovary must recover from prolonged suppression and redevelop its follicular population. Most mares successfully conceive and carry foals to term after the inactive ovary resumes function.

If both ovaries were removed (bilateral ovariectomy), the mare becomes permanently sterile but can still be used for riding or other purposes. Hormone replacement therapy is not typically needed as these mares do not show significant behavioral or health consequences from lack of ovarian hormones.

Recurrence and Malignancy

GCTs are nearly always benign, and metastasis is extremely rare. Recurrence is uncommon but can occur if the tumor was bilateral and only one ovary was removed, or if a new GCT develops on the remaining ovary years later. Routine follow-up is not typically required unless clinical signs recur.

Memory Aids for NAVLE

GCT = G.R.A.N.U.L.O.S.A.

G - Gonad tumor (ovary), most common ovarian tumor in mares

R - Reproductive dysfunction (anestrus, persistent estrus, irregular cycles)

A - AMH is gold standard test (98 percent sensitivity)

N - Normal contralateral ovary is SMALL and inactive (pathognomonic)

U - Unilateral in 95 percent of cases

L - Large ovary with multicystic honeycomb ultrasound pattern

O - Ovariectomy is curative treatment

S - Stallion-like behavior if testosterone elevated (50 percent of cases)

A - Activity returns in 6 to 8 months (contralateral ovary recovery time)

Hormone Test Sensitivity: A-I-T

AMH = 98 percent (Almost perfect)

Inhibin = 80 to 90 percent (Intermediate)

Testosterone = 48 percent (Terrible alone, but greater than 100 pg per mL is diagnostic)