Ovarian Cyst Differential Diagnosis: A Comprehensive Guide for Diagnosis and Management

Introduction

Ovarian cysts are sac-like structures filled with fluid that can be categorized as simple or complex. These are frequently discovered incidentally during routine physical examinations or imaging procedures. While many are benign, ovarian cysts can lead to significant complications such as rupture, hemorrhage, and ovarian torsion, all of which constitute gynecological emergencies. Therefore, accurate and timely diagnosis is crucial for effective management and to prevent potential morbidity and mortality. This article provides an in-depth review of the evaluation, treatment strategies, and potential complications associated with ovarian cysts, emphasizing the collaborative role of an interprofessional healthcare team in patient care.

The adnexa refers to the anatomical region adjacent to the uterus, primarily encompassing the ovaries and fallopian tubes. Although fallopian tubes are a key component of the adnexa, this discussion will center on the ovaries and the diverse types of cysts that can develop within them. The ovaries are positioned laterally to the uterus, supported by the utero-ovarian ligament and the infundibulopelvic ligament (also known as the suspensory ligament of the ovary), and are covered by the mesovarium, a part of the broad ligament. The ovaries receive their blood supply directly from the ovarian artery, branching off the aorta, with venous drainage differing between sides: the right ovarian vein flows into the inferior vena cava, while the left ovarian vein drains into the left renal vein. In women of reproductive age, the ovaries undergo monthly cycles, producing multiple follicles, with typically one dominant follicle maturing and proceeding to ovulation.

Ovulation can result in the formation of an ovarian cyst, a fluid-filled sac on one or both ovaries. Adnexal masses, including ovarian cysts, are common, affecting approximately 20% of women at some point in their lives. Over thirty distinct types of ovarian masses have been identified, and their management depends on the characteristics of the lesion, the patient’s age, and malignancy risk factors. In women during their reproductive years, the majority of ovarian cysts are functional and benign, often requiring no surgical intervention. However, complications such as pelvic pain, cyst rupture, hemorrhage, and ovarian torsion can occur, necessitating prompt medical attention and management.[1]

Etiology of Ovarian Cysts

The underlying causes of ovarian cysts and adnexal masses are varied, ranging from normal physiological processes (functional cysts like follicular or luteal cysts) to malignant ovarian conditions.[2] Ovarian cysts can develop at any age but are most prevalent during reproductive years due to endogenous hormone production, particularly in women who have started menstruating.[3] Simple cysts are the most common across all age groups, while complex cysts with both cystic and solid components, or completely solid lesions, carry a higher likelihood of malignancy compared to simple cysts. While most ovarian cysts are benign, advanced age is a significant independent risk factor. Postmenopausal women presenting with any type of ovarian cyst require careful evaluation and follow-up due to an increased risk of malignancy.[4, 5]

Risk factors associated with ovarian cyst formation include:

• Hormonal imbalances
• Menstrual cycle irregularities
• Early menarche
• Hypothyroidism [7]
• Tamoxifen therapy [3]
• Smoking and marijuana use, particularly in women with lower BMI [9]
• Use of fertility drugs (leading to theca lutein cysts)
• Polycystic ovary syndrome (PCOS)

Epidemiology of Ovarian Cysts

The precise prevalence of ovarian cysts remains uncertain because many cases are asymptomatic and undiagnosed. The reported prevalence varies depending on the population studied. It is estimated that approximately 4% of women will be hospitalized for ovarian cysts by the age of 65. A study of 335 asymptomatic women aged 24 to 40 found a 7.8% prevalence of adnexal lesions.[11] Research focusing on postmenopausal women showed a 2.5% prevalence of simple unilocular adnexal cysts.[12] In a broader survey of 33,739 premenopausal and postmenopausal women, 46.7% were found to have adnexal cysts on transvaginal ultrasound, with 63.2% of these abnormalities resolving in subsequent ultrasounds.[13, 14]

Notably, up to 18% of postmenopausal women may develop one or more Graafian follicles, which can appear as cysts on imaging.[11, 15, 16] The majority of these are benign. Mature cystic teratomas, also known as dermoid cysts, constitute over 10% of all ovarian neoplasms. Ovarian cysts are the most common type of tumor in infants and fetuses, with a prevalence exceeding 30%.[17] In the United States, ovarian carcinomas are diagnosed in over 21,000 women annually, resulting in approximately 14,600 deaths.

Pathophysiology of Ovarian Cysts

The normal menstrual cycle involves the follicular phase, marked by increased follicle-stimulating hormone (FSH) production. This hormonal surge leads to the selection of dominant follicles for ovulation. In a typical ovarian cycle, estrogen production from the dominant follicle triggers a luteinizing hormone (LH) surge, resulting in ovulation. Following ovulation, the remnants of the follicle develop into a corpus luteum, which produces progesterone, inhibiting further FSH and LH production. If pregnancy does not occur, progesterone levels decline, FSH and LH levels rise, and the cycle begins anew.

Functional Ovarian Cysts

Functional cysts are those that arise as a normal variation of the menstrual cycle. They are not neoplastic and are the most common type of ovarian cysts.

Follicular Cysts and Corpus Luteal Cysts

Follicular and corpus luteal cysts are classified as functional or physiological cysts, both occurring as part of the normal menstrual cycle. Follicular cysts form when a follicle fails to rupture and release an egg during ovulation. These cysts typically appear smooth, thin-walled, and unilocular on imaging. Their development in the follicular phase may be due to insufficient release of the ovum, potentially from excessive FSH stimulation or the absence of the usual LH surge prior to ovulation. Continuous hormonal stimulation can cause these cysts to grow, often exceeding 2.5 cm in diameter. The granulosa cells within follicular cysts can lead to excess estradiol production, which may result in decreased menstrual frequency.

The corpus luteum has a lifespan of 14 days in the absence of pregnancy. If fertilization occurs, the corpus luteum continues to secrete progesterone until around 14 weeks of gestation, at which point it regresses. If the corpus luteum does not regress, it can develop into a corpus luteal cyst, commonly reaching about 3 cm in size. Corpus luteal cysts can present as simple or complex, may have thick walls, and can contain internal debris. They are invariably present in pregnancy and usually resolve by the end of the first trimester. Both follicular and corpus luteal cysts can become hemorrhagic cysts. Generally, they are asymptomatic and resolve spontaneously without intervention.[18]

Theca Lutein Cysts

Theca lutein cysts are a type of functional cyst associated with high levels of human chorionic gonadotropin (hCG), leading to overstimulation of the ovaries. These are most commonly seen in pregnant women, particularly those with gestational trophoblastic disease, multiple gestations, or ovarian hyperstimulation syndrome.

Polycystic Ovary Syndrome (PCOS)

Polycystic ovary syndrome is a common endocrine disorder affecting 5% to 10% of women of reproductive age and is a leading cause of infertility. PCOS is frequently associated with conditions like diabetes mellitus and cardiovascular disease. In PCOS, the ovaries are characterized by multiple small follicular cysts and appear enlarged. This enlargement is due to excess androgen hormones, which cause cyst formation and ovarian enlargement.[19]

Neoplastic Ovarian Cysts

Neoplastic cysts arise from abnormal cell proliferation within the ovary and can be either benign or malignant. They can originate from the surface epithelium, with benign types including serous and mucinous tumors. Other cystic neoplastic lesions can involve stromal or germ cell elements. Stromal masses are more often solid, while germ cell tumors are frequently complex. Malignant cysts can arise from any ovarian subtype, most commonly from the surface epithelium. Epithelial malignancies include serous carcinoma, mucinous carcinoma, endometrioid carcinoma, clear cell carcinoma, and malignant Brenner tumors. Malignant germ cell tumors include immature teratoma, endodermal sinus tumors, embryonal carcinoma, and polyembryoma.

Dermoid cysts, or mature cystic teratomas, are unique neoplastic cysts containing elements from all three germ layers (ectoderm, mesoderm, and endoderm). They typically appear complex but can vary widely in appearance depending on the tissues they contain. Struma ovarii, a specialized teratoma predominantly composed of mature thyroid tissue, is found in about 5% of ovarian teratomas. Although dermoid cysts are usually benign, malignant transformation can occur in 1% to 2% of cases.[20, 21]

Endometriosis, the presence of endometrial tissue outside the uterus, commonly affects the ovaries. Endometriomas, frequently seen in endometriosis, develop from ectopic endometrial tissue growth and are often called chocolate cysts due to their content of dark, thick, aged blood. On ultrasound, they appear as complex masses with characteristic “ground glass” internal echoes. Endometriomas are classified into type I (small primary endometriomas from surface endometrial implants) and type II (arising from functional cysts invaded by endometriosis). While the risk of malignant transformation is generally low, endometriomas do increase this risk in women with endometriosis.[22, 23, 24]

History and Physical Examination in Ovarian Cyst Diagnosis

While many ovarian cysts are discovered incidentally during physical exams or pelvic imaging, a comprehensive medical history, with specific attention to gynecological history, family history, and a thorough physical examination, remains essential. Ovarian cysts can be asymptomatic or symptomatic. Symptoms may include unilateral lower abdominal pain or pressure, which can be intermittent or constant, and described as sharp or dull. Rupture of an ovarian cyst or ovarian torsion may present with a sudden onset of severe, acute pain, often accompanied by nausea and vomiting. Menstrual cycle irregularities and abnormal vaginal bleeding can also occur.[25]

Physical examination includes a bimanual pelvic exam to assess the ovaries for location, shape (regular or irregular), size, consistency, tenderness, and mobility. However, palpation of the ovaries can be challenging due to patient body habitus, examiner experience, and individual pelvic anatomy, limiting the diagnostic accuracy of pelvic examination alone for ovarian cysts.[5]

Evaluation and Diagnostic Modalities for Ovarian Cysts

When an ovarian mass is suspected, the initial step is to determine the patient’s menopausal status. For premenopausal women, a serum beta-hCG or urine pregnancy test should be performed. Once pregnancy is excluded, imaging is necessary for further evaluation. A complete blood count (CBC) can assess for anemia due to acute bleeding by checking hematocrit and hemoglobin levels. Urinalysis is recommended to rule out urinary tract infections and nephrolithiasis. Endocervical swabs may be collected to test for pelvic inflammatory disease. Cancer antigen 125 (CA-125) is a biomarker found on the cell membranes of both healthy ovarian tissue and ovarian cancer cells. A normal CA-125 level is less than 35 U/mL. Elevated CA-125 levels are found in approximately 85% of patients with epithelial ovarian cancer and about 50% of those with stage I cancer confined to the ovary. CA-125 levels are most clinically useful when combined with ultrasound in evaluating postmenopausal women with ovarian cysts.[11, 15]

Transvaginal ultrasonography is the primary imaging modality for initial evaluation due to the close proximity of the probe to the ovaries. It is crucial for differentiating between benign and malignant masses. Abdominal ultrasonography can be used adjunctively if pelvic anatomy is distorted by prior surgeries. Ultrasound assessment includes evaluating laterality, size, composition (cystic, solid, or mixed, septations, papillary excrescences, mural nodules), presence of pelvic free fluid, and blood flow using color Doppler. Ultrasound features suggestive of benign cysts, regardless of age, include thin, smooth walls, absence of septations or solid components, and no internal flow on color Doppler.

A critical concern in patients with pain and adnexal mass is ovarian torsion, which can lead to necrosis and ovarian loss. Importantly, normal blood flow on Doppler ultrasound does not rule out torsion. A case-control study showed normal Doppler flow in 27% of left ovarian torsion cases and 61% of right ovarian torsion cases, highlighting that intermittent torsion or the ovary’s dual blood supply can maintain flow despite torsion.[26]

Features raising suspicion for malignancy and warranting further investigation include cyst size over 10 cm, complex multilocular masses, papillary excrescences, solid components, irregularity, thick septations, ascites, and increased vascularity on color Doppler.[5] Additional imaging, such as magnetic resonance imaging (MRI) or computed tomography (CT), may be used but are not typically part of the initial evaluation. Gynecologic oncology consultation should be considered in cases of suspected malignancy.[27, 28, 29]

Differential Diagnosis of Abdominal Cysts

When considering the differential diagnosis of an abdominal cyst, and specifically an ovarian cyst, it is crucial to differentiate between gynecological and non-gynecological conditions. The location, patient history, and imaging characteristics are key to narrowing down the possibilities.

Gynecological Differential Diagnosis:

• Benign Ovarian Conditions:
  • Functional Cysts: Follicular cyst, corpus luteum cyst, hemorrhagic cyst, theca lutein cyst. These are often transient and related to the menstrual cycle.
  • Endometrioma: Cysts associated with endometriosis, often with characteristic “chocolate cyst” appearance on imaging.
  • Mature Teratoma (Dermoid Cyst): Benign germ cell tumor containing various tissues like fat, hair, teeth; often with a characteristic Rokitansky nodule on imaging.
  • Cystadenoma (Serous or Mucinous): Benign epithelial tumors, can be large and multilocular.
  • Para-tubal Cyst: Cysts located near the fallopian tube, distinct from the ovary itself.
  • Hydrosalpinx: Fluid-filled fallopian tube, may mimic an adnexal cyst.
  • Leiomyoma (Fibroid): Uterine fibroids, particularly pedunculated subserosal fibroids, can sometimes be mistaken for adnexal masses.
  • Tubo-ovarian Abscess (TOA): Inflammatory mass involving the ovary and fallopian tube, usually in the context of pelvic inflammatory disease.
• Malignant Ovarian Conditions:
  • Epithelial Carcinoma: Serous, mucinous, endometrioid, clear cell carcinomas; the most common type of ovarian cancer, often complex and solid on imaging.
  • Germ Cell Tumor: Dysgerminoma, endodermal sinus tumor, embryonal carcinoma, immature teratoma, choriocarcinoma; more common in younger women, can be complex and rapidly growing.
  • Sex Cord-Stromal Tumor: Granulosa cell tumor, Sertoli-Leydig cell tumor, fibroma, thecoma; often solid or mixed solid and cystic.
  • Metastatic Cancer: Ovarian metastases from other primary cancers (e.g., colon, breast, stomach).
• Other Gynecological Conditions:
  • Pelvic Inflammatory Disease (PID): Can present with adnexal tenderness and masses, often bilateral.
  • Ectopic Pregnancy: Pregnancy outside the uterus, typically in the fallopian tube, can present as an adnexal mass and is a critical differential in women of reproductive age.

Non-Gynecological Differential Diagnosis:

• Appendiceal Abscess: Abscess related to appendicitis, can present in the right lower quadrant and mimic an adnexal mass.
• Diverticular Abscess: Abscess associated with diverticulitis, typically in the left lower quadrant, can be mistaken for a pelvic mass.
• Pelvic Kidney: Ectopic kidney located in the pelvis, can be palpated as an abdominal mass.
• Gastrointestinal Cancers: Colon cancer, rectal cancer, can sometimes present as pelvic masses.
• Urinary Tract Infection (UTI) and Nephrolithiasis: While primarily urinary conditions, referred pain and associated symptoms might initially suggest a gynecological issue.
• Psoas Abscess: Abscess in the psoas muscle, can extend into the pelvis and mimic an adnexal mass.
• Lymphadenopathy: Enlarged pelvic lymph nodes due to infection or malignancy.
• Peritoneal Inclusion Cyst: Benign cysts formed by adhesions trapping peritoneal fluid, often multilocular and conform to pelvic structures.

This broad differential highlights the importance of a detailed clinical evaluation and appropriate imaging to accurately diagnose ovarian cysts and distinguish them from other abdominal and pelvic conditions.

Treatment and Management Strategies for Ovarian Cysts

Management of ovarian cysts is tailored to the patient’s age, menopausal status, cyst size, and the presence of features suggestive of malignancy. Unilocular cysts less than 10 cm in diameter are typically benign regardless of patient age. Asymptomatic patients with such cysts can often be managed conservatively with serial transvaginal ultrasounds, as most cysts resolve spontaneously without intervention. If a cyst persists through several menstrual cycles, it is less likely to be functional, and further evaluation is warranted.[30]

Fetal ovarian cysts are caused by hormonal stimulation and have been linked to maternal diabetes and fetal hypothyroidism. Most fetal ovarian cysts are small and resolve within the first few months of life, typically requiring no intervention. These cysts are usually diagnosed in the third trimester and often resolve 2 to 10 weeks postnatally.[8]

Most pregnancy-associated cysts, including corpus luteal and follicular cysts, resolve spontaneously by 14 to 16 weeks of gestation, allowing for conservative management.[31] Resolution is less likely for cysts larger than 5 cm or those with complex morphology. Simple cysts smaller than 6 cm have a malignancy risk of less than 1%.[32]

For endometriomas in women of all ages, follow-up sonograms are recommended at 6 to 12 weeks post-initial imaging, then annually until surgically removed. Dermoid cysts also warrant yearly ultrasound follow-up until surgical removal.

Surgical intervention is indicated for suspected ovarian torsion, persistent adnexal masses, acute abdominal pain unresponsive to conservative measures, and suspected malignancy. In premenopausal women, fertility preservation is a priority in surgical planning, and efforts are made to remove minimal ovarian tissue. Pregnant patients may also require surgery for cysts. While laparoscopy is generally safe across all trimesters, the second trimester is often considered the optimal time for surgery.[33]

Prognosis of Ovarian Cysts

Most ovarian cysts are benign, asymptomatic, and resolve spontaneously, leading to a favorable prognosis. Approximately 70% to 80% of functional follicular cysts resolve on their own. Although malignant transformation of benign ovarian cystadenomas has been suggested, it remains unproven. Low malignant potential tumors typically follow a benign course, with an overall 5-year survival rate of 86.2%.[31] Malignant changes can occur in rare cases of dermoid cysts (associated with a very poor prognosis) and endometriosis. If malignancy is suspected, the prognosis is generally poorer, as ovarian cancer is often diagnosed at advanced stages.

Complications of Ovarian Cysts

Three primary complications of ovarian cysts are considered gynecological emergencies:

• Ovarian Cyst Rupture: Cyst rupture can cause sudden, severe abdominal pain. Most ruptures are of functional cysts and cause mild to moderate symptoms, manageable with conservative treatment. However, some ruptures can lead to significant hemorrhage and hemodynamic instability.
• Ovarian Hemorrhage: Bleeding within a cyst can also cause pain and, in severe cases, lead to hemodynamic instability requiring medical intervention.
• Ovarian Torsion: Ovarian torsion, the fifth most common gynecological emergency, involves partial or complete twisting of the ovary on its pedicle, obstructing blood flow. Diagnosis is clinical, supported by history, physical exam, blood work, and imaging, and confirmed by laparoscopy. Current evidence favors a conservative laparoscopic approach, with detorsion of the ovary, with or without cystectomy, recommended to preserve fertility. [11]

Postoperative and Rehabilitation Care Following Ovarian Cyst Surgery

Surgical management of ovarian cysts may involve laparoscopy or laparotomy, each with advantages and disadvantages. Laparotomy is typically preferred in hemodynamically unstable patients due to faster surgical access and direct visualization, but it results in larger incisions, increased postoperative pain, longer hospital stays, and recovery times. Laparoscopy, while more time-consuming, involves smaller incisions, less risk of infection and blood loss compared to laparotomy. However, the longer surgery duration increases exposure to general anesthesia and the risk of internal organ and blood vessel damage. Hemodynamically stable patients undergoing laparoscopy are usually discharged on the same day with standard post-surgical precautions and scheduled follow-up.

Interprofessional Consultations in Ovarian Cyst Management

Effective management of patients with ovarian cysts requires a multidisciplinary approach involving:

• Obstetrician/Gynecologist
• Infertility and Reproductive Endocrinologist
• Gynecologic Oncologist
• General Surgeon
• Radiologist
• Pathologist

Cases with high risk of ovarian malignancy should be reviewed by a gynecologic oncologist for further assessment and optimal surgical planning. Guidelines help gynecologists determine when to refer patients with adnexal masses. Typically, referral to gynecologic oncology is indicated for postmenopausal women with elevated CA-125, premenopausal women with significantly elevated CA-125, ultrasound findings suggestive of malignancy, nodular or fixed pelvic masses, ascites, or evidence of abdominal or distant metastasis. Ultrasound features raising malignancy suspicion include cysts larger than 10 cm, cyst irregularity, high color Doppler flow, papillary or solid components, and ascites.[5]

Patient Education and Deterrence Strategies for Ovarian Cysts

Ovarian cysts are fluid-filled sacs within the ovary, commonly benign functional cysts that resolve spontaneously. They are often found incidentally during exams or imaging. In some cases, enlargement can cause ovarian torsion, a gynecological emergency requiring surgery due to compromised blood supply.

Rupture of ovarian cysts can also lead to life-threatening hemorrhage. Large cysts should be removed to prevent complications. Patients should seek prompt medical evaluation for sudden onset of unilateral moderate to severe sharp lower abdominal pain, especially if associated with nausea, vomiting, or strenuous activities like intercourse or exercise.

Enhancing Healthcare Team Outcomes in Ovarian Cyst Management

While most ovarian cysts are benign and resolve spontaneously, complications like rupture, hemorrhage, and torsion necessitate urgent medical or surgical intervention. Evaluation aims to identify the etiology of symptoms when ovarian cysts are present. Acute lower abdominal pain is a common emergency room presentation with varied causes. Accurate diagnosis can be challenging without appropriate imaging. Transvaginal ultrasound is the recommended first-line imaging for suspected or incidentally found pelvic masses. [Level 1]

Suspicious findings for malignancy include cyst size over 10 cm, ascites, papillary excrescences, solid components, irregularity, and high color Doppler flow. [Level 1]. Surgical intervention for mature teratomas or endometriomas is warranted if masses are large, symptomatic, growing, or malignancy is suspected. Expectant management requires follow-up surveillance.[28, 29] [Level 2]

Effective diagnosis and management of ovarian cysts require an interprofessional healthcare team including physicians (MDs and DOs), specialists, mid-level practitioners (NPs and PAs), and nurses, all sharing patient information and updates on status changes, developments, and treatment outcomes. This interprofessional approach improves patient outcomes and reduces adverse events. [Level 5]

Review Questions

Figure: Ovarian follicles and oocytes development stages, including a small primary follicle.

Figure: Illustration of an ovarian follicle during maturation, highlighting a cystic mature follicle.

Figure: Microscopic view of a cystadenofibroma of the ovary, a benign neoplasm.

Figure: Dermoid cyst of the ovary, characterized by mature teratoma with diverse tissue components like epidermis, dermis, and hair follicles.

Figure: Depiction of a dermoid cystic teratoma of the ovary, a common type of ovarian cyst.

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