Review Article. Struma Ovarii: a Mini

Int J Clin Exp Med 2018;11(10):10364-10371 www.ijcem.com /ISSN:1940-5901/IJCEM0070646

Review Article Struma ovarii: a mini review

Ting Zhang, Pingping Chen, Yuping Gao

Department of Assisted Reproduction, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shang- hai, China Received December 9, 2017; Accepted July 2, 2018; Epub October 15, 2018; Published October 30, 2018

Abstract: SO is a rare ovarian tumour with little clinical and imaging features. Most of the cases are benign and often associated with mature cystic teratoma. Increase of CA125 levels in the serum can potentially lead to a misdiagnosis of a malignant ovarian carcinoma preoperation. The diagnosis of a cystic struma ovarii is usually made on histopathology. Up to 5-10% of all cases of struma ovarii are reported to be malignant. Best treatment for benign struma is laparoscopic operation. Prognosis of benign strumosis and malignant struma ovarii without metastases is good. Malignant struma ovarii generally has a favorable prognosis while the prognosis of MSO with metastases is less favorable.

Keywords: Struma ovarii, papillary thyroid carcinoma, malignant struma ovarii

Introduction age incidence with mature cystic teratoma. Onset age of the disease is extensive, mostly in The monodermal teratoma struma ovarii (SO) women of fertile age with the peak age inci- was originally described by Bottlin in 1888 as dence in the fifth decade. It was found that 6% a rare form of ovarian tumor. Struma ovarii of the cases occur bilaterally [6] while most means ovarian goiter which originates from a cases occur in one side as more often affect single germ cell after the first meiotic division the left ovary [7, 8]. [1, 2] and is the most common type of monodermal teratoma in 3% of mature teratomas, The clinical symptom may include a non-specif- 0.3-1% of ovarian tumour [3], 5-20% of mature ic palpable pelvic mass and nearly 5% of cases teratoma has the component of thyroid tissue may present with hyperthyroidism [9, 10]. Non- [4] and only 2% of these cases were diagnos- specific symptoms are described like abdomi- ed SO. According to the World Health Organi- nal pain, back pain, abdominal distension, vagi- zation (WHO) classification, this disease was nal bleeding and frequent urination has also defined as ovarian goiter which comprises thy- been described. Acute severe abdominal pain roid tissue either entirely or predominantly (> may be caused by tumor rupture. 50%). Malignant struma ovarii is even rarer as occurring in less than 5% of cases and metas- About 17% of the patients [11] developed pseu- tases were seldom seen [5]. do-Meigs’ syndrome with pleural effusion and ascites. Raised cancer antigen (CA)-125 levels As to the low morbidity, lack of clinical and can also be found in a few cases [12]. CA125 is ultrasonographic features, misdiagnosis rate of a widely accepted tumor marker of ovarian car- SO before operation is high. Hence, radiological cinoma. This presentation may result in a mis- preoperative diagnosis is crucial for determin- diagnosis of malignant ovarian cancer in elder- ing appropriate management, especially in ly patients which lead to unnecessary exten- patients of reproductive age who need fertility sive surgery. The mechanism behind the raised preserving therapy. cancer antigen levels in cases pseudo-Meigs’ syndromes is still not well explained. However, Clinical features CA-125 can found to be elevated in both benign and malignant ovarian carcinoma which means SO is a rare ovarian tumor with no specific clini- this clinical phenomenon of little value in stru- cal manifestations (Table 1). It has the similar ma ovarii patients. Clinical and experimental features of struma ovarii

Table 1. Clinical and pathological features of SO Signs Macroscopic examination Scrape smears/frozen sections Pelvic mass Mostly < 10 cm in size Multicystic mass with lobulated surface* Hyperthyroidism in 5% cases Mixed cystic and solid nodular mass Sometimes thickened septic Pseudo-meigs’ syndrome in 17% cases Vascular networks Occasionally has a dilated thyroid follicle Raised CA125 in a few cases 3-10 mm of capsule wall thickness Normal-appearing thyroidal tissue composed of thyroid follicles* Tumor rupture in few cases Hemorrhage, necrosis, fibrosis May associate with hyper/hypoactivity of thyroid tissue/ adenomatous nodule/nodular goitre Non-specific symptons Green or (and) brown solid/gelatinous/ Non-specific appearance of epithelium cells with flattened transparent/liquid to cuboidal cells Dermoid background in non cystic tumors *Features of great value on pathological diagnose of SO.

Pathological features mass, the identification of foci of typical struma through ample sampling, or the association On macroscopic examination, most cases of with mature cystic teratoma. struma ovarri are solid with some extent of cystic, the tumors with predominantly or entirely The most common malignancy SO is papilla- cyst maybe lead to misdiagnose. The tumors ry thyroid carcinoma (PTC) (carcinoma of follicu- are some mixed cystic and solid nodular mass lar are second most frequent, some of these encapsulated and mostly less than 10 cm in may represent follicular variant of papillary car- size, with vascular networks, sometimes adh- cinoma) [4, 7]. erent to surrounding tissues; The capsule wall thickness are mostly of 3-10 mm, contain br- Preoperative diagnosis of SO is difficult as it own or green-brown solid, gelatinous mass, lacks clear clinical syndromes. Most of the transparent, green, or brown liquids. Hemorrh- cases are benign and often associated with age, necrosis and fibrosis may be present. The mature cystic teratoma. Ignoring of the pres- dermoid background is found in some non-cys- ence of small carcinoid lesions that are diag- tic tumors. nosed only after pathological examination often occurs. Scrape smears and frozen sections are quite important to the accurate diagnose of ovarian Radiological images tumors and decision of surgical plan. Ultrasonography Typically, SO appears like a multicystic mass with lobulated surface and sometimes by thick- The ultrasound features of a struma ovarii are ened septic or cyst walls, occasionally has a quite indistinct, such as mostly unilateral tu- dilated thyroid follicle representing thyroid tis- mors, mixed cystic and solid mass, unilocular sue. The typical consists of normal-appearing or multilocular with clear boundary. On trans- thyroidal tissue composed of thyroid follicles vaginal ultrasonography, struma ovarii typical- and often is associated with mature cystic tera- ly appears as cystic tumors containing one toma. Changes of the thyroid tissue may occa- or more well circumscribed roundish solid ar- sionally associate with hyperactivity, hypoac- eas with smooth contour named as “struma tivity, or have the appearance of an adenoma- pearls” [14]. Although struma ovarii presents tous nodule or nodular goitre [13]. In cystic with a variety of non-specific appearances and struma, the epithelium cells lining the cyst may usually manifests as a multilocular cystic ovar- have a non-specific appearance with flatten- ian mass with solid components of various ed to cuboidal cells. The diagnostic difficulty of amounts, the ultrasound typically demonst- many cystic tumors is due to the non-specific rates these non-specific heterogeneous solid histological appearance (Table 1). cystic features. Doppler results were described by Savelli [14] as differing between dermo- Clues to the correct diagnosis of SO may inclu- id cysts and struma ovarii. The blood flow of de the detection of thyroid follicles in the cyst struma ovarii was detected in the central part wall or in fibrous septa separating locules of of the mass while in mature cystic teratomas

10365 Int J Clin Exp Med 2018;11(10):10364-10371 Clinical and experimental features of struma ovarii

Figure 1. Genetic al- the thymoglobulin and thyr- terations of papillary oid hormones in the follicular carcinoma arising in thyroids that could attenua- struma ovarii (PCSO) reported recent years. te the X-ray significantly [15, 16]. ④ The cyst wall and septum are usually thicker and about 0.3 to 1 cm, but the wall of the cyst is smooth, and the wall and septum are often calcified.⑤ Imaging following an intravenous contrast agent is known to dem- blood flow was detected only at the periphery of onstrate marked enhancement of the thick the ovary. septations and locally thickened wall seen in struma ovarii. The solid components, corresp- Computed tomography onding microscopically to thyroid tissue, also demonstrate strong enhancement. It may be Findings are generally non-specific on CT scan related to the solid part of SO, which is com- and demonstrates the complex appearance posed of thyroid tissue and stroma rich in blo- with multiple cystic and solid areas, reflecting od vessels and fibers [13, 17]. ⑥ SO was al- the gross pathological appearance of the ways complicated with small amount of ascit- struma. es. Almost no distant metastasis of benign CT findings of struma ovarii are characterized lesions, distant metastasis of malignant lesi- by the presence of high attenuation area and ons is also rare. calcifications [15]. The high-density cysts might Magnetic resonance imaging be a characteristic feature of struma ovarii on CT. The CT features could show solid, cystic, or The struma has features overlapping with tho- cystic-solid characteristics. Cystic-solid is the se of malignant ovarian epithelial tumours, as most frequent type while the solid type is the it presents either as a unilateral complex ad- least on CT scan. Unlike the most common nexal mass often associated with ascites, or as types of teratoma, struma ovarii does not dem- a multi-cystic mass with solid components and onstrate lipid material on either CT or MRI [8]. When struma ovarii is accompanied by foci of multiple cystic locules. Thick septations, mea- fatty tissue, they can be considered as areas of suring 3-10 mm. dermoid cyst associated with struma ovarii On MR imaging, the signal intensity of the va- [16]. In these circumstances, the presence of rious solid components varies. The SO cyst fl- dermoid cyst can be a strong clue to suspect uid signals are complicated, showing low sign- struma ovarii. Recognition of these manifesta- al in T1W1 and high signal in T2W1 [18]. MR tions is helpful in the diagnosis of this tumor. findings include a multicystic mass with a mu- In summary, CT scan has such manifestations, ltilobulated surface, some solid components ① Cystic-solid mass mostly occurred unilater- representing thyroid tissue including thicken- ally, solid mass is rare. ② Tumor mostly present ed septi or cyst walls and cystic components a lobulated shape with clear boundary, usually showing a variety of signal intensities on both the diameter of OS mass is less than 10 cm, T1- and T2-weighted images [16, 18]. The cys- occasionally over 20 cm. ③ The density of sin- tic components occasionally have loculi of low gle cystic mass is usually uniform, and the intensity on T2-weighted images and the punc- density of cystic density in polycystic type is dif- tuate foci of high intensity on T1-weighted imag- ferent, which is generally higher than the den- es. The solid components are of low signal sity of bladder fluid, high attenuation areas intensity on T2-weighted images and interme- and calcifications in the solid components of diate signal intensity on T1-weighted images. the struma are common findings, It has been The cystic spaces, on the other hand, demon- hypothesised that the appearance of high-den- strated both high and low signal intensity on T1- sity values from CT scan are caused by both and T2-weighted images. This pattern of signal

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Table 2. Radiological image features Ultrasonography Mostly unilateral tumors; mixed cystic and solid mass; typically appears as ostruma pearls Computed tomography Mostly Cystic-solid type, solid mass is rare; uniform density; high-density cysts might be a characteristic feature; does not demonstrate lipid material; smooth cyst wall, calcified septum; marked enhancement of the thick septations/solid components/thyroid tissue with contrast agent; always show small amount of ascites Magnetic resonance imaging Varies signal intensity*; low signal in T1W1 and high in T2W1 of cyst fluid; variety of signal intensities on T1-/ T2-weighted images of thyroid tissue/thickened septi/cyst walls; very low intensity on T2-weighted MR and no enhancement on contrast-enhanced MR of cystic areas *Radiological image features of great diagnostic value. intensity on T1- and T2-weighted imaging was ty tissue and other primary ovarian cancer, found to be due to the thick, highly viscous, endometriosis, metastatic tumors, and tubo- gelatinous colloid material in large follicles of ovarian abscess. the struma. The areas of very low intensity on T2-weighted images were thought to be cystic, Differentiation of benign and malignant because they did not reveal any enhancement struma ovarii on contrast-enhanced MR studies. This may be of great diagnostic value. Joja et al. [18] st- In total, up to 5-10% of all cases of struma ova- ated that the variety of signal intensities seen rii are reported to be malignant, usually in the on MR images in the cystic components de- 6th or 7th decade of life. The diagnosis of ma- pends on the degree of condensation of thyro- lignant struma ovarii is usually based on his- globulin and thyroid hormones, and it now rec- tological features of the resected ovary, as no ognised that this variable signal intensity is specific imaging features are available to dete- highly characteristic of struma ovarii. ct malignant struma ovarii (MSO). There is no universally accepted standard for the diagno- Clinical diagnosis sis of MSO. As in the thyroid gland, papillary carcinoma is the most common histological SO is a rare ovarian tumour with no clinical type of MSO accounting for 70% of cases and and ultrasound specific features. Increase of of these one third are follicular variant papillary CA125 levels in the serum can potentially lead carcinomas. Papillary carcinoma arising in stru- to a misdiagnosis of a malignant ovarian ca- ma ovarii (PCSO) can be clinically malignant in rcinoma preoperation [14]. The diagnosis of the absence of conventional histological fea- a cystic struma ovarii is usually made on his- tures of malignancy, most such lesions demon- topathology. strate follicular growth patterns and lack papillary cytological features. Criteria for malig- SO is mainly composed of thyroid follicles, nancy in struma ovarii are the same as those sometimes characterized by small papillary of a thyroid carcinoma. Indicated by the histo- hyperplasia or small follicles, so diagnosis is logical classification of WHO in 2003, nuclear generally not difficult. The diagnostic criteria features such as nuclear grooves are more include ① the mass is entirely composed of clearly visible on scrape smears and their ab- thyroid tissue ② Teratoma with goiter, including sence rules out a papillary carcinoma. In addi- thyroid composition accounted for more than tion, follicular carcinomas have capsular bre- 50% ③ or the symptom of hyperthyroidism aches and vascular invasion. Although diagno- occurs while thyroid composition of mass is sis of papillary thyroid carcinoma in malignant less than 50% ④ thyroid tissue can be recog- ovarian goiter is definite, diagnosis of follicular nized by naked eyes in the mature teratoma carcinoma requires vascular and/or capsular [19]. In these criteria, ①, ② and ③ are com- invasion. Whether these criteria used for the monly accepted by specialists. thyroid gland are applicable to the cases of struma ovarii is still controversial [20]. Imaging does not allow the differentiation of non-functioning struma ovarii from other cys- Immunohistochemistry is frequently used to tic masses. When struma ovarii is not associ- support a diagnosis of malignancy generally, or ated with hyperthyroidism, the differential diag- papillary carcinoma more specifically, using nosis includes: mucous or serous ovarian cyst- HBME-1, CK19 and CD56. Recently, absent adenoma, mature cystic teratoma without fat- CD56 expression has also been found to be

10367 Int J Clin Exp Med 2018;11(10):10364-10371 Clinical and experimental features of struma ovarii highly sensitive and specific for papillary thy- matosis with or without lymph node and/or dis- roid carcinoma [21, 22]. CK and HBME-1 are tant metastasis. characteristically positive in papillary thyroid carcinoma. Immunohistochemical staining wi- Therapy th cytokeratin (CK) 19 and HBME-1 (Hector Battifora mesothelial cell 1) may help to con- The gold standard treatment is surgery and firm the diagnosis of PCSO. It should be noted prognosis is excellent. The best treatment for that none of these antibodies are completely benign struma is laparoscopic operation. Com- sensitive or specific, but they have proven valu- plete removal of the tumor under laparoscope able in diagnostic practice. However, the appli- can not only remove the lesion, but also mini- cation of these three antibodies in combination mize the damage to the patient and recover is not known in PCSO. quickly after operation. If the tumor is com- plete, smooth and without malignant compo- Primary thyroid carcinomas have been found to nent, resection of the ovary and fallopian tube harbor a variety of genetic alterations like the or cyst removal alone are usually performed. BRAF, RAS (KRAS, NRAS, and HRAS), PIK3CA, During the operation, cysts should be removed and RET genes, including point mutations and totally, so as to avoid the omission and recur- rearrangements [23]. BRAF mutations are seen rence of the disease. Flushing the abdominal in 40-45% of papillary thyroid carcinoma and cavity and absorb all the fat/hair may help to up to 98% are V600E mutations. The V600E recover the intraperitoneal environment. Ca- mutation and other closely located mutations reful operation should be done in order to (K601E and TV599_600M deletion) have also reduce normal ovarian tissue damage. For wo- been identified in cases of PCSO. There are iso- men with fertility requirements, laparoscopic lated reports of NRAS and HRAS mutations in cystectomy can significantly reduce postopera- these tumors [23]. Novel mutations in BRAF tive adhesions and infertility due to adhesions and KRAS were identified in A. Tan’s research and pelvic pain. [24] in two cases and while additional larger studies are required, the findings suggested Little is known about malignant struma ovarii that there may be greater mutational diversity due to its rarity and accordingly there are few in PCSO than in eutopic thyroid papillary carci- guidelines to manage its treatment [26, 27]. noma. Data remain extremely limited on the Various treatment strategies have been sug- molecular changes in MSO including PCSO gested, but no treatment guidelines have been (Figure 1). established. The intensity of treatment is a sig- nificant issue for clinicians to consider. This For ovarian lesions which exceed the ovarian may include pelvic surgery, thyroidectomy and lesion itself, there is no consensus about the radioactive iodine (I131), which must be bal- ovarian struma with the dissemination of the anced against the risks of infertility and the low abdominal cavity, the greater omentum and rate of metastasis. A comprehensive assess- the surrounding organs. There is a difference in ment of the thyroid gland should be carried out understanding of ovarian goiter with benign to remove the metastasis of primary thyroid changes beyond the ovaries and surrounding tumors once malignant ovarian goiter was diag- disseminated lenses. Roth [19] gave two expla- nosed. In general, there is lack of consensus on nations for this problem. One explanation is the management of malignant struma ovarii that the implant is due to rupture of the cap- (MSO) or papillary carcinoma arising in struma sule of ovarian goiter or a mature cystic tera- ovarii (PCSO), although some authors have sug- toma with thyroid components. Another exp- gested thyroidectomy and I131 therapy, particu- lanation suggested that this may be caused larly for patients with gross extra-ovarian exten- by the spread of highly differentiated follicular sion or distant metastases [28, 29]. carcinoma. One year later, Roth [25] described a new entity, highly differentiated follicul- The surgical treatment of MSO is the main ar carcinoma of ovarian origin (HDFCO), whi- treatment which can be treated via total ab- ch is characterized by extraovarian dissemina- dominal hysterectomy and bilateral salpingo- tion of thyroid elements that histologically oophorectomy. The aggressive surgical man- resembles normal thyroid tissue. This entity agement followed by radioiodine therapy is comprises previously known peritoneal stru- best to reduce recurrence risk and optimize

10368 Int J Clin Exp Med 2018;11(10):10364-10371 Clinical and experimental features of struma ovarii survival. For women wishing to retain fertility, Prognosis unilateral salpingo-oophorectomy may still be a feasible option in the absence of extracapsular After treatment, the prognosis of benign stru- extension and distant metastases. mosis and malignant struma ovarii without metastases is good. If ascites and/or pleural An adjuvant treatment technique that has been effusion are present, they usually disappear suggested for residual, metastatic or recurrent after surgery. Malignant struma ovarii general- disease of malignant struma is radioiodine ly has a favorable prognosis with overall sur- therapy, which has been reported to result in vival of 92, 85 and 79%, at 5, 10 and 25 years favourable outcomes [30]. In patients present- [33]. The prognosis of MSO with metastases ing with multiple metastatic lesions, or for is less favorable. It has been suggested that those who absorb radioiodine poorly, external BRAF mutation-positive papillary thyroid can- beam radiation has been proposed [31]. cers, most commonly V600E, may show ad- verse prognostic features including invasive How to avoid misdiagnosis growth and lymph node metastasis and have worse clinical outcomes compared to papillary OS is difficult to diagnose preoperatively for the thyroid carcinomas which are negative for following reasons. First of all, the incidence of these mutations. The average duration of ini- this disease is low, and the clinical and imaging tial recurrence is 4 years, Because of the risk features are absent (Table 2). Second, the inci- of long-term recurrence [29], long-term follow- dence of hyperthyroidism is low. Preoperative up is required. examinations usually do not perform a specific examination of thyroid function and thyroid Strumal carcinoid of the ovary is a low-grade composition. Finally, the tumor itself is com- malignancy with slow growth. It was reported posed of cystic and solid components, contain- [34] that the malignant transformation rate is ing lipid, hair and skeletal components, which less than 0.1% and has a good prognosis. In a are difficult to identify with mature cystic tera- very rare occasion, strumal carcinoid can lead toma. Radiologically, a benign ovarian mass to metastasis [35]. Early surgical resection of presenting with ascites and raised cancer anti- stromal carcinoid can achieve the purpose of gen (CA)-125 levels can be misdiagnosed as a radical resection. In follicular thyroid carcinoma malignant ovarian tumour [32]. In such cases, a (FTC), mutations in the ras gene predict poor correct intraoperative diagnosis can prevent prognosis as the mutation rate of K-ras gene is extensive surgery. about 9%.

Diagnosis must be made by pathological exami- Cases with histological benign tumors have nation as diagnosis by naked eyes intraopera- better prognosis than those of histological ma- tive is not reliable. In pathological examination, lignant cases, and even if disseminated, the especially during the frozen section pathologi- prognosis is still good. It is also related to the cal examination, the tumor including the cap- extent of adhesions and the size of the tum- sule should be completely removed so as to or. Thyroglobulin can be used as an indicator avoid missed diagnosis. Struma ovarii contain- for the detection of postoperative tumor recur- ing thyroid type carcinoma must be distin- rence [36]. guished from rare cases of papillary or follicular Acknowledgements thyroid carcinoma metastatic to the ovary which are mainly characterized by cervical This study was supported by Programs Fou- lymph node metastasis, and less hematoge- ndation of Xinhua hospital (Relationship be- nous metastasis. Since most malignant goiter tween PCOS patients’ EDCs expression and is the pathological diagnosis, the extent of pri- their outcome of IVF-ET, 2016-2017), National mary surgical resection is usually not enough. Natural Science Foundation of China (81571- Hence, staging of reoperation to evaluate 435, 81401260), and Foundation of Shanghai lymph node and other site metastasis is often Municipal Science and Technology Committee unavoidable. Ovarian goiter sometimes has (17411966200). many morphological changes, a careful search for thyroid follicles should be undertaken. Disclosure of conflict of interest Immunohistochemical staining for thyroglobulin in difficult cases is recommended. None.

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