Cystic Teratoma

Etiology

Multiple studies have identified some risk factors that have been linked to mature cystic teratomas. They include the following: late menarche with menstrual irregularities, alcohol abuse, history of cystic teratoma in the past, fewer pregnancies, infertility, exercise during adolescence (related to anovulatory menstrual cycles).[3]

Epidemiology

Cystic teratomas are the most common ovarian germ cell tumors comprising 20% of all the ovarian tumors in adults and half of all ovarian neoplasms in children and are usually benign. On the contrary, malignancy is a rare occurrence constituting about 1%.[4][5] They are most predominant in women in their second and third decades of life as the most common benign tumor less than 45 years of age. According to one of the largest studies involving 460,000 females, it was observed that the annual incidence rate of CT was 1.2 to 14.2 cases per 100,000.[6][3] 

Over the period of decades, several multicenter studies have observed different rates of incidence of benign cystic teratomas such as Marchetti observed a 20% occurrence of all ovarian tumors, while a large study by Blackwell et al. reported the occurrence to be 5%. Due to the rarity of this tumor, literature is skewed by either isolated case reports or small multicenter groups of cases. Thus leading to a broader range of incidence.

Pathophysiology

Since the discovery of grotesque teratoma lesions which resembled deformed fetus, several theories emerged based on concepts from religious to scientific assumptions. Some of the interesting ideas involved the likely cause of witchcraft, perverted gestation, immoral acts, and ingestion of hair and bones embedded in the ovaries. It was later believed that these tumors originated from degenerated ova, in situ impregnation of ovum within the ovary (fetus in the fetus). Evidence of dermoid cyst in virgins, post-menopausal women, males, and extra ovarian sites (stomach, mediastinum) convinced the biologists that structures like bone, teeth could develop within a tumor instead of its origin as a result of aberrant fertilization.[2] 

Analysis of biochemical and cytogenetic data showed that cystic teratomas of the ovary are parthenogenetic tumors formed by spontaneous asexual development of an unfertilized ovum after the first meiotic division. Another explanation is the alteration of blastodermal elements in a fertilized ovum. Despite all these theories, the pathophysiology of teratoma formation is still obscure and the focus of many experimental studies.[7] An extraordinary feature of the teratoma is its ability to not only differentiate into tissue cells but also develop into organ systems. For example, respiratory epithelium with blocks of cartilage and bone fragments developing into digits or partial limb at rare instances.[8]

Histopathology

Mature cystic teratomas are unilocular in  88% of the cases with a cystic cavity lined by squamous epithelium. The cyst is predominantly filled with sebaceous material that is liquid at body temperature and solidifies at room temperature. The size of these tumors varies from very tiny cystic masses to as large as greater than 39cm, with 80% measuring 10cm or less.[9] These tumors are most frequently unilateral, involving the right ovary (72%), and bilateral in 12%.[4] 

On gross appearance, these lesions do not have a characteristic shape or size as it depends on the microscopic heterogeneity of the contents. Hair, teeth, and bones are easily identifiable on gross examination. Microscopic examination of the contents confirms the diagnosis by identifying tissues derived from the following germ cell layers: Ectodermal tissue (epithelium and neural tissue), Mesodermal tissue (muscle, fat, bone, cartilage), and endodermal tissue ( thyroid tissue, gastrointestinal epithelium).[10]

History and Physical

Cystic teratomas are usually asymptomatic or can have minimal symptoms. Various studies have reported asymptomatic tumor rates to be 6-65% at the time of diagnosis. They are often discovered as an incidental finding on radiographic studies, during a physical exam or pelvic/abdominal surgery for any other pathology. The next most common symptom reported at the time of presentation is lower abdominal pain with a reported rate of 44 to 47%, followed by palpable abdominal or pelvic mass.[11] 

Some patients present with increasing abdominal girth. Gastrointestinal or urinary symptoms can develop with increasing tumor size causing compression or invasion of the adjacent structures. Symptoms like fever, cachexia, severe abdominal pain, vaginal bleeding can also occur in advanced disease.[12] 

In the case of ovarian torsion, one of the most common complications of cystic teratoma, the patient presents with an acute abdomen (sudden abdominal pain, nausea, vomiting), requiring urgent management. On physical examination, bimanual palpation of the ovaries to determine the presence or absence of adnexal masses, uterus size, and abdominal tenderness should be assessed. Therefore, a detailed history with more emphasis on gynecological history and a thorough physical exam, abdominal and pelvic exam, in particular, plays a crucial role in early diagnosis and management of a patient presenting with the above symptoms.

Evaluation

Initial Assessment: It involves an initial assessment of the patient, including vitals, detailed history, physical exam with more emphasis on abdominal and pelvic exam, followed by complete blood count, complete metabolic panel, and a pregnancy test. Mature cystic teratomas do not have any specific diagnostic tumor marker.  Serum tumor markers, in particular, alpha-fetoprotein (AFP), human chorionic gonadotrophin (hCG), and lactate dehydrogenase (LDH) have shown to play some role in diagnosis and follow up. Cystic teratomas are usually asymptomatic and often discovered on workup for other conditions. However, in patients presenting with abdominal pain, discomfort, and increasing abdominal girth, imaging plays an important role in further workup. 

Imaging: Although plain radiographs may show radiopaque bodies due to calcifications during work-up for urinary or intestinal pathology, cysts with very little or no calcification can be easily missed. Ultrasound is the preferred initial radiological investigation for the evaluation of adnexal mass. Cystic teratoma appears as a heterogeneous mass with echogenic focus causing acoustic shadowing due to calcification, sebum, and hair. Fat fluid and hair fluid levels are more specific features. Some other peculiar sonographic findings include the Rokitansky nodule, iceberg sign, dot-dash pattern(dermoid mesh), and floating balls sign. Transvaginal ultrasound is superior to abdominal ultrasound for screening for cystic teratomas with a sensitivity of 57.9% and specificity of 99.7%. It has proven to be as accurate as MRI in the identification and characterization of ovarian cystic teratomas.[13][14] 

In torsion, a whirlpool sign with a twisted vascular pedicle is seen on color Doppler ultrasound.[15] Ovarian teratomas can also be overlooked on abdominal ultrasound if it appears similar to bowel gas. CT abdomen and pelvis is believed to be the best modality for evaluation of an adnexal mass, especially for pre-operative assessment.[16] 

Histopathological evaluation remains the gold standard for diagnosis.

Treatment / Management

The definitive treatment of cystic teratoma is surgery. Due to the highest incidence of cystic teratomas in women of reproductive age, the major concern is preserving fertility and minimizing post-surgical adhesion formation. Size of the mass, ultrasound characteristics, involvement of adjacent structures, risk of malignancy, and most importantly, patient’s symptoms and wish to retain fertility are factors determining the best management plan. Options include the following:

Surveillance: Pre-menopausal women who wish to be pregnant and have a cyst size of lower than 6cm are recommended conservative management for as long as the growth rate of the cyst is <2cm/year. In cystic teratoma during pregnancy, surveillance is recommended as far as the patient is not having acute symptoms.[17][18]

Surgical management: In premenopausal women, symptomatic dermoid lesions less than 5 cm are preferably removed by simple laparoscopic cystectomy, rather than removing the entire ovary. Cysts larger than 5 to 6 cm and have involved the entire ovary with distortion of its structure should be removed by oophorectomy. Oophorectomy should be considered in postmenopausal women with multiple cysts. Histological examination of the surgical specimen confirms the diagnosis, including staging in case of carcinoma. In such cases, complete resection with bilateral salpingo-oophorectomy, hysterectomy, and even platinum-based chemotherapy is the mainstay of treatment.[19] Laparoscopy is the gold standard technique for surgical management. (B2)

Laparoscopic surgery has a diagnostic advantage in which peritoneal liquid sampling and exploration of the abdominopelvic cavity for possible malignancy can be done to assess the involvement of adjacent structures.[20] Laparotomy is recommended in complex cases like massive complex mass, cyst rupture with an acute emergency, or malignancy with advanced stage. When suspicion of malignant transformation is high, management includes a frozen section analysis of the tissue specimen by a pathologist during the surgery.(B2)

Laparotomy may be given priority over the laparoscopic approach if there is a risk of spillage of cyst contents. As soon as the pathological diagnosis of malignancy is established, the next step is to complete tumor excision with staging to determine prognosis and further treatment.[21] Intraoperative spillage of cystic teratoma contents has an estimated incidence of 0.2% with laparoscopic excision of the mass. Chemical irritation by the contents can increase the risk of adhesion formation. The use of Endobag (impermeable endoscopic sac) in one randomized controlled trial demonstrated a reduction of spillage from 46% to 3.7% of the cases.[22] Recurrence risk post laparoscopic cystectomy has also been observed, ranging from 2 to 10 years after surgery. Due to the risk of involvement of the contralateral ovary with occult cystic teratoma, careful inspection of the ovary is essential. Some patients also develop other germ cell tumors seen from 6 months to 6 years. Therefore, premenopausal patients managed with cystectomy should be followed for recurrence and other germ cell tumors.[22][23](B2)

Differential Diagnosis

Differential Diagnosis of cystic teratoma encompasses broad categories of conditions depending on the origin and pathological nature of the mass. The classification is based on its appearance as an adnexal mass. It is as follows: 

Non-gynecological

1. Benign: Renal cyst, peritoneal cyst, bladder diverticulum, pelvic kidney, peritoneal inclusion cyst, diverticular abscess, peritoneal/retroperitoneal abscess.
2. Malignant: retroperitoneal sarcoma, metastasis (lung, lymphoma, etc.), gastrointestinal cancer. 

Gynecological

1. Benign: ectopic pregnancy, hemorrhagic ovarian cyst, tubo-ovarian abscess, pedunculated fibroid, polycystic ovary, simple cyst, endometrioma, cystadenoma.
2. Malignant: Endometrial carcinoma, ovarian sarcoma, sex cord/stromal tumor, ovarian germ cell tumor, Kruckenberg tumor.

Prognosis

Prognosis largely depends upon the extent of the disease and its complications. Benign cystic teratomas generally have an excellent prognosis after surgical management with some risk of recurrence in 2 to 10 years. On the contrary cystic teratomas with malignant transformation have variable outcomes depending upon the stage, growth pattern, and vascular invasion of the tumor.[24] According to one study by Peterson et al. 75%, the 5-year survival rate was seen in unruptured stage I tumors.[1] Pooled data by Kashimura et al. showed a 5-year survival rate in stage I: 50%, 5-year survival rate in stage II: 25%, 5-year survival rate in stage III: 12%, and no survivors in stage IV.[25]

Complications

Ovarian cystic teratomas can be associated with a wide spectrum of complications. Timely and accurate diagnosis significantly reduces morbidity and mortality. Common complications of cystic teratomas are listed below;

1. Torsion: One of the well-established complications of ovarian tumors is its rotation around the pedicle (supportive ligament), compromising its own blood flow leading to gangrenous or hemorrhagic infarction. The torsion incidence ranges from 3 to 21 %, most commonly occurring in the group 5 to 15 cm in size.[2][26] Intermediate sized teratomas are more prone to torsion as compared to small or large ones. Mild twisting along the pedicle can also affect venous drainage resulting in congestion and ultimately hemorrhage within the cyst itself.
2. Rupture: Although not a very common occurrence, the risk of rupture is 1 to 4% in ovarian teratomas. Leakage of contents of the cyst-like sebaceous fluid, desquamated epithelial cells, bone, or teeth into the peritoneal cavity can lead to acute or chronic peritonitis.[13] Rupture of the cyst into adjacent structures like the intestine or rectum may result in bone expulsion, hair, and teeth via the anus.
3. Infection: The risk of infection in cystic teratoma is about 1 to 4%. The route of infection can be hematogenous, lymphomatous, or by direct extension from the adjacent structures like intestines. Infection can also predispose the cyst to form adhesions or even rupture in severe cases.[26] 
4. Adhesions: Occasionally, the cyst may become dependant on the blood supply of the omentum or surrounding structures by forming contralateral circulation and completely get detached from its pedicle, hence called “parasitic dermoid.” Chronic inflammation can lead to a worsening of adhesions, increasing the risk of intestinal obstruction.
5. Malignant transformation:  Malignant transformation has been reported to occur in 1 to 3% of all cases of cystic teratoma between 30 and 70 years of age, with a higher incidence in patients between 40 to 60 years of age. Of those, squamous cell carcinoma was the most common (50%).[27] The other 50% involved transitional cell carcinoma, malignant melanoma, choriocarcinoma, carcinoids, sarcomas, and adenocarcinoma. Patients with tumor size >10mm were seen to be at higher risk of developing malignant transformation.[24][28] Limited capsular malignancy has a better prognosis.
6. Gliomatosis peritonei: Implantation of glial tissue on the visceral or peritoneal lining in a metastatic manner appear as grey or white nodules, 1 to 3 mm in diameter, and are scattered throughout the peritoneal cavity. Due to their indistinguishable appearance from peritoneal carcinomatosis and tuberculous peritonitis, histological evaluation is necessary for diagnosis.[29] 
7. Anti-N-methyl-D-aspartate receptor (NMDAR)encephalitis: An infrequent auto-immune complication may occur with neuropsychiatric symptoms. Anti-NMDAR antibodies target NMDA receptors resulting in the progressive decline of synaptic functions. Early recognition and prompt treatment with surgery improve the clinical outcome.[30]