Borderline ovarian tumors (BOTs)

Definition

Borderline ovarian tumors are neoplasia of the female gonads with low malignant potential, occupying an intermediate position between malignant and benign neoplasms. Do not have pathognomonic symptomatology; most often, patients complain of pelvic pain, decreased appetite, nausea, and abdominal bloating. Diagnosis includes gynecological examination, ultrasound, and determination of the level of tumor marker titers; the final diagnosis is established after surgical intervention.  

General information

Borderline ovarian tumors (atypical proliferative tumors) are epithelial neoplasms characterized by marked proliferation and cellular and nuclear atypia inherent to cancer but without signs of destructive invasion of the stroma and solid growth. These tumor formations are characterized by recurrence, extraovarian spread, most often affecting the peritoneum, rarely (in 7-29% of cases) – lymph nodes, very rarely – distant organs. “Metastases” of borderline tumors are called implants. Implants can be invasive (with signs of malignization) and non-invasive. Serous (50-55%) and mucinous (40-45%) neoplasms are the most common among borderline neoplasias. Borderline tumors account for 10-15% of the structure of all ovarian neoplasia and are most often found in women 30-50 years old.

Reasons

The etiology of borderline ovarian tumors is unknown. It is assumed that the main reasons for the development of the disease are an increase in the number of ovulatory cycles per life period, disruption of gonadotropic hormone secretion by the pituitary gland and sex hormones by the ovaries, and disorders of immune regulation. In contrast to the causes, risk factors of pathology are sufficiently studied, including:

• Peculiarities of reproductive anamnesis. The probability of ovarian borderline neoplasia is significantly increased by infertility – this condition is present in 30-35% of women at the time of diagnosis of neoplasia. Other risk factors include unrealized reproductive function, shortened lactation (less than six months), early menarche (before 11 years), late (after 55 years) onset of postmenopause, early (before 19 years) or late (after 35 years) age of first pregnancy, abortion.
• Genital abnormalities. The risk of atypical proliferative endometrioid tumors significantly increases ovarian endometriosis. Gynecologic surgeries for uterine myoma, ectopic pregnancy, and purulent inflammation of the appendages can provoke the development of neoplasm due to impaired ovarian tropism.
• Endocrine disorders. Pathologies of endocrine glands, metabolic and neural regulation disorders, and medications lead to the occurrence of ovarian tumors. Risk factors: hyperandrogenism of any genesis, pituitary adenoma, adrenal tumors, hypo- and hyperthyroidism, severe damage to the liver parenchyma, estrogen replacement therapy at menopause, taking contraceptives with high estrogen content.
• Infections. It is believed that the probability of tumor occurrence correlates with the number of adnexitis and chronic inflammation, mainly caused by specific (sexually transmitted) infectious agents. An important role is attributed to intracellular microorganisms – pathogenic types of mycoplasma and ureaplasma.

Predisposing conditions include diseases and conditions that weaken the immune response (diabetes mellitus, severe infections, poisoning), obesity (including those that occurred in childhood and adolescence), and increased fat consumption (especially at a young age). The emergence of tumors potentiates prolonged psycho-emotional stress.

Classification

Considering the histological type, the following types of borderline neoplasia are distinguished: serous (atypical proliferative serous tumor, non-invasive highly differentiated serous carcinoma), mucinous, endometrioid, clear cell, Brenner’s tumor, and mixed. Serous tumors are more often observed in women of reproductive age, with a frequency of 35-45% affecting both ovaries and 30% spreading to the peritoneum, and in a quarter of cases, invasive implants are found. In the mucinous type of peritoneal involvement, the incidence of implants is 10%. Other histotypes are characterized by localized unilateral lesions.

Symptoms

The symptoms of the disease are diverse and variable. The most commonly reported pain syndrome is dull, aching pain in the lower abdomen and navel region, radiating to the hips, shins, and lower back. General symptoms include weakness, malaise, weight loss, rapid fatigue, loss of efficiency, sleep disturbance, and fever. Gastrointestinal tract symptoms include nausea, unpleasant sensations in the mouth, a feeling of gastric overflow when consuming even small amounts of food, belching, vomiting, and constipation. On the part of the urinary system with tumor growth, frequent urges and difficulty urinating are registered. Up to 37% of borderline ovarian neoplasms occur without any subjective sensations.

Complications

The main threatening and most frequent complication of borderline neoplasia (mainly serous) is desmoplasia – the ability of epithelial cells of the implants to reproduce connective tissue. This process results in massive foci of fibrosis in the abdominal cavity, compressing the intestine, which leads to irreversible impairment of its function and intestinal obstruction, often causing the death of the patient.

Another dangerous complication is the malignization of the tumor or implants. Recurrences with malignant transformation are possible, characterized by all the properties of adenocarcinoma – aggressive local growth and a high probability of metastasis to lymph nodes and distant organs. Malignant transformation is quite rare and causes lethal outcomes related to the tumor and its treatment only in 0.7% of cases.

Diagnosis

Diagnostic tests are ordered by a gynecologist or oncologist. Histologic verification of the diagnosis is performed intraoperatively during curative surgery. An essential role in diagnosis belongs to the pathomorphologist since the establishment of histologic distinction between invasive cancer and atypical hyperplasia is often difficult and requires high qualifications and professional experience. Preoperative diagnostic measures include:

• Ultrasonography. Abdominal and transvaginal examination is performed. Ultrasound of the pelvic organs and abdominal cavity can detect hidden (nonpalpable) ovary tumors, disseminates of the peritoneum, diaphragm, liver and spleen, and suggest a borderline risk of malignancy of the formation.
• Immunochemical analysis. Increased levels of oncological markers (CA 125, CA 19-9, HE-4, REA) indirectly indicate tumor growth. A significant increase of CA 125, HE-4 titer is characteristic of serous neoplasms, and an increase of CA19-9 – for mucinous tumors.

Additionally, radiography of the chest cavity, CT and MRI of the pelvis and abdomen, colonoscopy, and puncture biopsy of the Douglas space (to exclude cancer) may be prescribed. Differential diagnosis is carried out with primary and metastatic ovarian cancer, benign tumors, retention cysts of the ovaries, tumors of the uterus (more often with myoma, sarcoma) and intestine, and purulent inflammation of the appendages.

Treatment of borderline ovarian tumors

The only method of treatment is surgery. Since neoplasia is mainly similar to malignant neoplasms, surgery should be performed by a gynecologic oncologist – this improves the prognosis and reduces the likelihood of recurrence. Intervention is carried out through laparotomic or laparoscopic access. Chemotherapy is not prescribed due to ineffectiveness (possibly due to the low proliferative activity of such neoplasms), according to some clinical studies, worsens the outcome of the disease.

The extent of surgery depends on the stage of neoplasia and the age of the patient; young women are treated to preserve fertility whenever possible. Patients of reproductive age at any stage may undergo resection of the ovary, provided there is healthy tissue in it. In case of unilateral total damage to the organ, a unilateral adnexectomy is performed, in case of bilateral – removal of both uterine appendages or hysterovariectomy. Postmenopausal women with tumors of stages I-IIIA with one ovary are treated with unilateral tubovariectomy, with bilateral lesions – bilateral (sometimes with removal of the uterus), with a more widespread process – extirpation of the uterus with appendages.

In case of peritoneal involvement, large visualizable nodules are removed. The primary operation necessarily includes surgical staging to clarify the spread of the process and histological characterization of the implants. For this purpose, all patients undergo resection of the contralateral ovary and the greater omentum and a peritoneal biopsy. According to the results of histologic examination of the samples, dynamic study or repeated surgery is prescribed. If areas with reduced histologic differentiation – foci of invasive growth – are detected, treatment protocols for invasive cancer, including chemotherapy and radiation therapy, are applied.

All these treatment options are available in more than 700 hospitals worldwide (https://doctor.global/results/diseases/borderline-ovarian-tumors-bots). For example, Bilateral adnexectomy can be done in 25 clinics across Turkey for an approximate price of $3.7 K (https://doctor.global/results/asia/turkey/all-cities/all-specializations/procedures/bilateral-adnexectomy). 

Prognosis and prevention

The prognosis of borderline ovarian tumors is favorable. In women with the first stage of the disease, the five-year survival rate is 99%, the ten-year survival rate is 97%, with the second stage – 98% and 90%, respectively, with the third stage – 96% and 88%, with the fourth stage – 77% and 69%. Recurrences most often occur two years after treatment and are observed in 35-50% of cases, after hysterovariectomy occur twice or three times less often than after organ-preserving operations. Recurrences without malignant transformation do not worsen the prognosis. Invasive implants reduce the ten-year survival rate by 25-30%.

Primary prevention measures include rational contraception, realization of reproductive function, timely treatment of hormonal disorders, and inflammatory diseases of the genital organs. Secondary prevention consists of lifelong observation by an oncologist-gynecologist with sonographic and immunochemical control: within five years after surgery, every 3-6 months, an ultrasound of abdominal and pelvic organs and analysis of tumor-associated markers are prescribed, and these studies are performed annually.