Continuing Education Activity

Epithelial ovarian neoplasms account for 60% of all ovarian tumors and include benign, borderline, and malignant lesions. Ovarian cystadenomas are benign epithelial tumors with an excellent prognosis and are classified as serous, mucinous, endometrioid, clear cell, or seromucinous according to the 2014 World Health Organization classification. Serous cystadenomas represent approximately two-thirds of benign epithelial ovarian tumors, while mucinous cystadenomas account for about 25%; the remaining subtypes are uncommon. Many cystadenomas are discovered incidentally during evaluation for other gynecologic conditions, although larger masses may cause symptoms related to mass effect or ovarian torsion. Clinical history, presentation, serologic testing, and imaging findings may suggest a benign process, but definitive diagnosis requires histopathologic evaluation following surgical removal. This activity reviews the pathology, presentation, diagnosis, treatment, and interprofessional management of ovarian cystadenomas.

Objectives:

• Compare the subtypes of ovarian cystadenomas.
• Evaluate the presentation of ovarian cystadenomas.
• Assess the treatment options for ovarian cystadenomas.
• Collaborate with members of the interprofessional team, including gynecologists and subspecialists, radiologists, and pathologists, for efficient, timely, and appropriate care of patients presenting with findings of ovarian cystadenomas.

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Introduction

Epithelial neoplasms of the ovary account for 60% of all ovarian tumors and 40% of benign tumors.[1] They are classified as benign, borderline, or malignant. Ovarian cystadenomas are benign epithelial neoplasms that carry an excellent prognosis. Two of the most frequent types of cystadenomas are serous and mucinous subtypes. Endometrioid, clear cell, and seromucinous cystadenomas are rare [Danforth's: 10th Edition of Danforth's Obstetrics and Gynecology, Ch 62]. Despite advances in imaging, the diagnosis remains by histopathological examination after surgical resection. This review will focus on the etiology, clinical presentation, diagnosis, and treatment strategies for ovarian cystadenomas.

Etiology

Serous cystadenomas are the most common benign epithelial ovarian tumors. They are derived from epithelial inclusions that typically arise from fallopian tube epithelium. Hyperplastic expansion of these cells leads to the formation of serous cystadenomas, typically polyclonal and less likely monoclonal in cellularity. In contrast to serous borderline and serous carcinomas, serous cystadenomas lack mutations in BRAF and KRAS.[2]

Mucinous cystadenomas are associated with KRAS mutations in 58% of tumors.[3] KRAS mutational status is also present in invasive mucinous neoplasms, supporting the idea that these tumors are on a continuum with malignant transformation.[4] HER2 amplification is greater in benign mucinous cystadenomas than in mucinous borderline tumors.[5] A subset of mucinous cystadenomas contains Brenner components, consisting of transitional cells arising from the lining of the bladder and urinary tract, implying that a subset of these tumors originates from surface epithelium. Association with dermoid cysts indicates that some are of germ cell origin as well.[6] 

Seromucinous cystadenomas, endometrioid cystadenomas, and c lear cell cystadenomas  are thought to develop from endometriotic cysts and endometriosis.[7][8]

Epidemiology

Serous cystadenomas account for 50-70% of all benign ovarian tumors and the majority of all serous ovarian tumors [Danforth's: 10th Edition of Danforth's Obstetrics and Gynecology, Ch 62].[9] They occur in adult women of all ages, with a mean age of 40 years. They are bilateral in 20% of cases [Danforth's: 10th Edition of Danforth's Obstetrics and Gynecology, Ch 62]. 

Mucinous cystadenomas account for 80% of ovarian mucinous tumors and 25% of all benign ovarian tumors [Danforth's: 10th Edition of Danforth's Obstetrics and Gynecology, Ch 62].[10] Mucinous cystadenomas of the ovary occur mainly during the third to sixth decades, though they may also occur in the extremes of ages, with case reports of presentation in both younger women and post-menopausal women.[11][12] They are unilateral in 95% of cases [Danforth's: 10th Edition of Danforth's Obstetrics and Gynecology, Ch 62]. 

Seromucinous cystadenomas occur in adults with a peak incidence in the peri- and post-menopausal age group.[13][8] They account for approximately 1% of all benign epithelial ovarian tumors [Kurman R.J et al, International Agency for Research on Cancer. World Health Organization. WHO Classification of Tumours of Female Reproductive Organs. International Agency for Research on Cancer; Lyon, France: 2014. p. 307].[14]

Endometrioid cystadenomas are a rare type of ovarian tumor. Less than 1% of all benign ovarian tumors are benign endometroid tumors [Diagnostic Gynecologic and Obstetric Pathology, Third Edition; Ch 25. p 865-948]. They often occur in pre-menopausal women with a peak incidence in the third decade.[15] Endometrioid tumors may correlate with endometriosis.[16][17]

Clear cell cystadenomas are rare, with few cases reported in the literature.[15] They may also correlate with endometriosis. The average age of presentation is in the seventh decade. [Diagnostic Gynecologic and Obstetric Pathology, Third Edition; Ch 25. p 865-948] 

Pathophysiology

Ovarian cystadenomas are benign epithelial tumors that originate from the ovarian surface epithelium or cortical inclusion cysts. They are characterized by neoplastic epithelial proliferation with cystic dilatation and accumulation of secretory fluid, leading to the formation of uni- or multilocular cystic masses. Histologically, serous cystadenomas demonstrate tubal-type epithelial differentiation, whereas mucinous cystadenomas show endocervical-type differentiation. These lesions remain benign due to the absence of stromal invasion and significant cytologic atypia.

Histopathology

Serous Cystadenoma

Macroscopic findings:

Serous cystadenomas range in size from 1 to more than 30 cm in greatest dimension (mean of 10 cm). They have a smooth outer surface and contain one or more thin-walled cysts filled with clear, watery fluid appearing hypoechoic on transvaginal ultrasound.[18] Serous cystadenomas are usually unilocular but may be multilocular [Danforth's: 10th Edition of Danforth's Obstetrics and Gynecology, Ch 62]. 

Image: Ovary serous cystadenoma

Histopathology:

Serous cystadenomas are composed of cysts and papillae lined by a single layer of non-stratified or stratified cuboidal to columnar cells resembling fallopian tube epithelium.[18] Psammoma bodies may be present. Atypia, mitotic activity, and cellular proliferation are absent.[19] [WHO Classification of Tumours Female Genital Tumours. ISBN: 978-92-832-4504-9].[18]

Image: Serous cystadenoma, multiloculated cyst wall with monostratified serous epithelium. 10x H/E stain.

Immunohistochemistry:

The immunohistochemical profile of serous cystadenoma is similar to that of common ovarian surface epithelium and tubal epithelium, including positivity for cytokeratin, epithelial membrane antigen, estrogen receptor (ER), PAX8 positivity, and no abnormal p53 expression.[20] [Kurman RJ, Ellenson LH, Ronnett BM. Blaustein’s Pathology of the Female Genital Tract. New York, NY: Springer; 2011:1246 -- book].[21] 

Mucinous Cystadenoma

Macroscopic findings: 

Mucinous cystadenomas have a smooth surface and are usually multilocular but sometimes unilocular [Danforth's: 10th Edition of Danforth's Obstetrics and Gynecology, Ch 62]. They range in size from a few centimeters to greater than 30 cm, with a mean of greater than 10 cm. The content is typically mucoid.[10][22]

Image: Mucinous cystadenoma of ovary

Histopathology:

Mucinous cystadenomas are composed of multiple cysts and glands lined by columnar epithelium resembling gastric endocervical or gastrointestinal epithelium with basal nuclei that secrete mucin [Danforth's: 10th Edition of Danforth's Obstetrics and Gynecology, Ch 62].[10] There is no cytologic atypia or mitotic figures. 

Immunohistochemistry:

Often, mucinous cystadenomas stain positive for CK7 and CK20, but this is non-specific.[23] There is an association with positive MUC5AC staining, with invasive mucinous neoplasms expressing low levels of this marker.[24]

Seromucinous Cystadenoma

Macroscopic findings: 

Grossly, seromucinous cystadenomas present without loculations or as unilocular cysts with smooth surfaces. They may contain serous or mucinous fluid.[14]

Histopathology:

Histologically, as defined by the World Health Organization (WHO) criteria, these tumors consist of at least 10% of two different Müllerian cell types, though often they are only associated with endocervical-type epithelium. They are lined by a variable mixture of single-layer serous and mucinous cells, typically endocervical-type, sometimes with foci of endometroid-type epithelium.[8][14] 

Endometrioid Cystadenoma

Macroscopic findings:

These cysts can range in size and are typically unilocular, with possible areas of hemorrhage. The cyst fluid can be clear, mucoid, or hemorrhagic [Diagnostic Gynecologic and Obstetric Pathology, Third Edition; Ch 25. p 865-948].

Histopathology: 

Rare reported endometrioid cystadenomas are lined by benign stratified columnar or cuboidal cells, which can resemble endometrioid epithelium. There is no atypia. [Diagnostic Gynecologic and Obstetric Pathology, Third Edition; Ch 25. p 865-948].[25]

Clear Cell Cystadenoma

Macroscopic findings:

Clear cell cystadenomas are typically solid tumors with small cysts dispersed throughout, containing clear fluid. Greater than 90% of benign clear cell tumors are unilateral and can be as large as 20 cm. [Diagnostic Gynecologic and Obstetric Pathology, Third Edition; Ch 25. p 865-948]

Histopathology:

Clear cell cystadenomas are composed of non-pseudostratified columnar to cuboidal cells with clear cytoplasm due to glycogen or mucin. There is no nuclear atypia [Diagnostic Gynecologic and Obstetric Pathology, Third Edition; Ch 25. p 865-948]. 

History and Physical

Ovarian cystadenomas ranging in size from 1 to 3 cm are usually incidental findings and reveal themselves during an ultrasound investigation of another gynecologic disorder.[26] The symptoms and signs associated with large tumors most commonly include bloating, pelvic pain, and discomfort. More acute presentations may suggest cyst rupture or, more significantly, ovarian torsion, which is a surgical emergency.[18] Physical exam should consist of a thorough abdominal exam, lymph node evaluation, and pelvic exam. Larger lesions may be palpated on bimanual exam as fullness in the right or left lower quadrants. Family history should be interrogated to determine an individual's hereditary risk of ovarian cancer. Findings of ovarian cancer are non-specific and should be taken in conjunction with a patient's complete clinical picture.[27]

Evaluation

Serum Markers

Serum CA-125 assay is a useful tool that may help distinguish benign from malignant ovarian masses. Other markers to consider in the workup of an adnexal mass include beta-hCG, L-lactate dehydrogenase, alpha-fetoprotein, inhibin, and human epididymis protein 4.[28] The combination of normal serum markers, imaging findings consistent with benign disease, and a patient's clinical findings helps to exclude ovarian cancer.[26]

Imaging Studies

Several imaging techniques are useful for the diagnosis of ovarian cystadenomas. They include pelvic/transvaginal ultrasound (US), computed tomography (CT), and magnetic resonance imaging (MRI).[29][26] Pelvic US is the first-line imaging technique as it is easily accessible, inexpensive, and can evaluate an ovarian cyst's size, components, vascularity, and the presence or absence of free fluid in the pelvis. CT and MRI are not first-line imaging studies, though MRI may be better than US at distinguishing malignant masses, with a better specificity and accuracy.[30]

The features that are more suggestive of a benign ovarian neoplasm include:

• Unilocular
• Single or a few thin septations
• Thin walls
• Size less than 10 cm
• Absence of papillary projections
• Absence of vascularity [26]

Histopathology

The definitive diagnosis of ovarian cystadenomas is based on histopathological examination of the surgical specimen. Correlation with pathology is important to distinguish the diagnosis of these benign tumors from borderline tumors or ovarian carcinoma.

Treatment / Management

The management of ovarian cystadenomas depends on the following factors [31]:

• Symptoms
• Size of the cyst
• Age of the patient
• Medical history
• Menopausal state of the patient

Observation is an appropriate choice for patients without concern for malignant disease. Pelvic ultrasonography is the imaging study of choice for monitoring of benign disease. Lack of interval growth is reassuring. In patients over 50 years, it has been shown that the risk of ovarian cancer is less than 0.5% in patients with stable adnexal masses for 6 weeks after initial imaging was performed.[32] The time frame for the duration of surveillance has not been established, though interval ultrasonography may be performed at intervals greater than one year, given their slow growth.[33]

Ovarian cystectomy and sometimes unilateral salpingo-oophorectomy are the definitive treatments for ovarian cystadenomas. Minimally invasive approaches such as laparoscopic or robotic surgery are preferred. Surgical management should be considered for patients with symptomatic disease, a size greater than 10 cm, or features suspicious of malignant disease. When considering treatment of benign cystadenomas, the low inherent risk of the mass itself may be outweighed by the risk of surgery in patients with multiple comorbidities. Special consideration should be taken for patients of childbearing age who desire future fertility. Clinical recurrence is uncommon and reflects either incomplete resection or a new primary tumor. 

Differential Diagnosis

Thorough clinical, imaging, and laboratory evaluations are important to rule out malignant disease in patients presenting with an adnexal mass. Infectious processes should also be ruled out to exclude diagnoses like tubo-ovarian abscess. Other considerations for benign disease include functional cysts, paratubal cysts, hydrosalpinx, leiomyomas, Müllerian anomalies, adenofibromas, dermoid cysts, or endometriomas. Imaging findings, along with tumor markers, are useful in the differentiation of these diagnoses from cystadenomas. Borderline tumors may present similarly to cystadenomas, though they have a higher risk of transformation to malignancy and recurrence.[34] Other ovarian neoplasms that should be considered include epithelial ovarian cancer, germ cell tumors, stromal cell tumors, and metastatic tumors of different origins [Diagnostic Gynecologic and Obstetric Pathology, Third Edition; Ch 25. p 865-948].

Prognosis

All ovarian cystadenomas are benign lesions, with a low risk of recurrence and an excellent prognosis.[29][11]

Complications

Cystadenomas of the ovary are benign lesions that rarely recur after complete resection. The more significant complications of unresected ovarian cystadenomas include rupture of the cyst or ovarian torsion (twisting of the ovary, a surgical emergency). If surgery is pursued in women of childbearing age, fertility impacts should be considered with manipulation of the ovarian stroma. There is a risk of pseudomyxoma peritonei developing, in which mucin accumulates in the abdominal cavity, including gelatinous ascites and peritoneal implants, if a mucinous cystadenoma ruptures.[35]

Deterrence and Patient Education

Patient education for ovarian cystadenoma should emphasize that these tumors are usually benign and often have an excellent prognosis with appropriate evaluation and management. Patients should be counseled on symptoms such as pelvic pain, bloating, or increasing abdominal girth and advised to seek care for sudden or worsening symptoms that may indicate complications such as torsion or rupture. Although prevention is not well established, regular gynecologic care and prompt evaluation of persistent pelvic symptoms may help support early diagnosis and treatment.

While the definitive treatment of ovarian cystadenomas is surgical management, if the cyst is incidentally found in an asymptomatic patient and noted to be small, without features concerning for malignancy, the morbidity of surgical intervention should be strongly weighed against the low inherent risk of a small asymptomatic ovarian cystadenoma. 

Enhancing Healthcare Team Outcomes

Providing patient-centered care for individuals with ovarian cystadenomas requires an interprofessional approach involving physicians, advanced practice providers, nurses, radiologists, and pathologists. Accurate diagnosis depends on integration of clinical presentation, imaging findings, and ultimately histopathologic evaluation, requiring close collaboration between radiology, gynecology, and pathology teams. Clinicians must be able to appropriately risk-stratify adnexal masses, distinguishing benign-appearing cystadenomas from lesions requiring oncologic referral or surgical intervention. In many cases, conservative management is appropriate, making evidence-based decision-making and avoidance of unnecessary surgery an important component of care.

Clear communication among team members is essential to ensure appropriate follow-up, timely imaging interpretation, and consistent patient counseling regarding prognosis and management options. When surgical management is indicated, coordination with gynecologic surgery and pathology ensures accurate diagnosis and optimal outcomes. This interprofessional, patient-centered approach supports safe, efficient care while minimizing overtreatment and ensuring appropriate management of ovarian cystadenomas.

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Disclosure: Christina Rutherford declares no relevant financial relationships with ineligible companies.

Disclosure: Christopher Tarney declares no relevant financial relationships with ineligible companies.

Disclosure: Karen Carlson declares no relevant financial relationships with ineligible companies.